Indole derivatives useful for the treatment of CNS disorders

ABSTRACT

The present invention relates to dopamine D 4  ligands having the general formula I  
                 
 
     wherein  
     (a) one of Y 1  and Y 2  is N, which is bound to Y 4 , and the other of Y 1  and Y 2  is CO, CS, SO, or SO 2  and Y 4  is CH 2 ;  
     (b) one of Y 1  and Y 2  is N, which is bound to Y 4 , and the other of Y 1  and Y 2  is CH 2  and Y 4  is CO, CS, SO or SO 2 ; or  
     (c) one of Y 1  and Y 2  is N, which is bound to Y 4 , and the other of Y 1  and Y 2  is CH 2  and Y 4  is CH 2 ;  
     Y 3 is Z—CH 2 , CH 2 —Z or CH 2 CH 2 , and Z is O or S; provided that when Y 1  is N, Y 3  may not be Z—CH 2 ;  
     W is a bond or an O, S, CO, CS, SO or SO 2  group;  
     n is 0-5, m is 0-5 and m+n is 1-10; provided that when W is O or S, then n≧2 and m≧1; when W is CO, CS, SO or SO 2 , then n≧1 and m≧1;  
     X is C, CH or N; provided that when X is C, the dotted line indicates a bond, and when X is N or CH, the dotted line is absent;  
     R 1 -R 9  are independently selected from hydrogen, halogen, cyano, nitro, amino, hydroxy, C 1-6 -alkyl-amino, di-C 1-6 -alkyl-amino, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 1-6  alkoxy, C 1-6 -alkylthio, C 1-6 -alkyl substituted with hydroxy or thiol, C 3-8 -cycloalkyl, C 3-8 -cycloalkyl-C 1-6 -alkyl, acyl, thioacyl, aryl, trifluoromethyl, trifluoromethylsulfonyl, and C 1-6  alkylsulfonyl;  
     R 10  is hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 1-6 -alkyl substituted with hydroxy or thiol, C 3-8 -cycloalkyl, C 3-8 -cycloalkyl-C 1-6 -alkyl, aryl, aryl-C 1-6 -alkyl, acyl, thioacyl, C 1-6 -alkylsulfonyl, trifluoromethylsulfonyl or arylsulfonyl, or a pharmaceutically acceptable acid addition salt thereof.  
     The compounds of the invention are potent dopamine D 4  receptor ligands.

[0001] This application is a continuation of International applicationno. PCT/DK01/00406, filed Jun. 13, 2001, and claims priority under 35U.S.C. §119 of U.S. provisional application serial No. 60/212,445, filedJun. 16, 2000. The prior applications are hereby incorporated byreference, in their entirety.

FIELD OF THE INVENTION

[0002] The present invention relates to a novel class of indolederivatives having affinity for the dopamine D₄ receptor. The compoundshave antagonistic effect at the dopamine D₄ receptor and are thereforeuseful in the treatment of certain psychiatric and neurologic disorders,in particular psychoses. Some of the compounds also have affinity forthe dopamine D₃ receptor, the 5-HT_(2A) receptor and/or the 5-HT_(2C)receptor and some of the compounds are serotonin reuptake inhibitors.

BACKGROUND OF THE INVENTION

[0003] Dopamine D₄ ligands related to the compounds of the invention areknown from WO 98/28293. The indane and dihydroindole derivativesdisclosed therein have the general formula

[0004] wherein A is an indole and Y is a group completing an indane, ora dihydroindole and the other substituents are as defined in theapplication.

[0005] WO 00/23441 discloses compounds of the general formula

[0006] wherein the substituents R₁, R₂, R₃, m, n and p are as defined inthe application. The compounds are said to show high affinity todopamine D₂ receptors and are also said to be serotonin reuptakeinhibitors. The compounds are claimed to be useful for the treatment ofschizophrenia and other psychotic disorders.

[0007] Other compounds structurally related to the compounds of theinvention are described in WO 99/58525. The compounds disclosed thereinare said to be 5-HT_(2A) ligands and serotonin reuptake inhibitors andhave the general formula

[0008] wherein the substituents are as defined in the application. Thecompounds are said to be useful for the treatment of schizophrenia.

[0009] WO 00/31074 relates to compounds having the formula

[0010] wherein X is CO or SO₂ and Y is N—R⁴ or CR⁴R⁵ and thesubstitutents are as described in the application. The compounds aresaid to be active at the 5-HT_(2A) receptor, to have 5-HT reuptakeinhibiting activity and to enhance 5-HT release.

[0011] The applications, WO 94/18197, EP 329168, WO 93/16073, EP 732332,WO98/37893 and WO 95/11680, disclose dopamine D₄ ligands, which, likethe compounds of the present invention, are substitutedtetrahydroquinolinone and tetrahydroisoquinolinone derivatives. However,these compounds do not contain an indole as the compounds of theinvention. The compounds are said to be dopamine D₄ ligands useful asantipsychotics. The compounds of WO 93/16073 are also claimed to haveantagonistic activity at 5-HT₂ receptors.

[0012] Dopamine D₄ receptors belong to the dopamine D₂ subfamily ofreceptors, which is considered to be responsible for the antipsychoticeffect of neuroleptics. The side effects of neuroleptic drugs, whichprimarily exert their effect via antagonism of D₂ receptors, are knownto be due to D₂ receptor antagonism in the striatal regions of thebrain. However, dopamine D₄ receptors are primarily located in areas ofthe brain other than striatum, suggesting that antagonists of thedopamine D₄ receptor will be devoid of extrapyramidal side effects. Thisis illustrated by the antipsychotic clozapine, which exerts higheraffinity for D₄ than D₂ receptors, and is lacking extrapyramidal sideeffects (Van Tol et al. Nature 1991, 350, 610; Hadley Medicinal ResearchReviews 1996, 16, 507-526 and Sanner Exp. Opin. Ther. Patents 1998, 8,383-393).

[0013] A number of D₄ ligands, which were postulated to be selective D₄receptor antagonists (L-745,879 and U-101958), have been shown to possesantipsychotic potential (Mansbach et al. Psychopharmacology 1998, 135,194-200). However, recently it has been reported that these compoundsare partial D₄ receptor agonists in various in vitro efficacy assays(Gazi et al. Br. J. Pharmacol. 1998, 124, 889-896 and Gazi et al. Br. J.Pharmacol. 1999, 128, 613-620). Furthermore, it was shown thatclozapine, which is an effective antipsychotic, is a silent antagonist(Gazi et al. Br. J. Pharmacol. 1999, 128, 613-620).

[0014] Consequently, D₄ ligands, which are partial D₄ receptor agonistsor antagonists, may have beneficial effects against psychoses.

[0015] Dopamine D₄ antagonists may also be useful for the treatment ofcognitive deficits (Jentsch et al. Psychopharmacology 1999, 142, 78-84).

[0016] Further, evidence for a genetic association between the“primarily inattentive” subtype of ADHD and a tandem duplicationpolymorphism in the gene encoding the dopamine D₄ receptor has beenpublished (McCracken et al. Mol. Psychiat. 2000, 5, 531-536). Thisclearly indicates a link between the dopamine D₄ receptor and ADHD, andligands affecting this receptor may be useful for the treatment of thisparticular disorder

[0017] Dopamine D₃ receptors also belong to the dopamine D₂ subfamily ofreceptors, and they are preferentially located in the limbic brainregions (Sokoloff et al. Nature 1990, 347, 146-151), such as the nucleusaccumbens, where dopamine receptor blockade has been associated withantipsychotic activity (Willner Int. Clinical Psychopharmacology 1997,12, 297-308). Furthermore, an elevation of the level of D₃ receptors inthe limbic part of schizophrenic brains has been reported (Gurevich etal. Arch Gen Psychiatry 1997, 54, 225-32). Therefore, D₃ receptorantagonists may offer the potential for an effective antipsychotictherapy, free of the extrapyramidal side effects of the classicalantipsychotic drugs, which primarily exert their effect by blockade ofD₂ receptors (Shafer et al. Psychopharmacology 1998, 135, 1-16 andSchwartz et al. Brain Research Reviews 2000, 31, 277-287).

[0018] Moreover, D₃ receptor blockade results in a slight stimulation inthe prefrontal cortex (Merchant et al. Cerebral Cortex 1996, 6,561-570), which could be beneficial against negative symptoms andcognitive deficits associated with schizophrenia. In addition, D₃antagonists can reverse D₂ antagonist-induced EPS (Millan et al. Eur. J.Pharmacol. 1997, 321, R7-R9) and do not cause changes in prolactin(Reavill et al. J. Pharmacol. Exp. Ther. 2000, 294, 1154-1165).Consequently, D₃ antagonistic properties of an antipsychotic drug couldreduce the negative symptoms and cognitive deficits and result in animproved side effect profile with respect to EPS and hormonal changes.

[0019] Dopamine D₃ agonists have also been considered relevant in thetreatment of schizophrenia (Wustow et al. Current Pharmaceutical Design1997, 3, 391-404).

[0020] Various effects are known with respect to compounds, which areligands at the different serotonin receptor subtypes. As regards the5-HT_(2A) receptor, which was previously referred to as the 5-HT₂receptor, the following effects have been reported, e.g.:

[0021] Antidepressive effect and improvement of the sleep quality (Meertet al. Drug. Dev. Res. 1989, 18, 119), reduction of the negativesymptoms of schizophrenia and of extrapyramidal side effects caused bytreatment with classical neuroleptics in schizophrenic patients (GeldersBritish J. Psychiatry 1989, 155 (suppl. 5), 33). Furthermore, selective5-HT_(2A) antagonists could be effective in the prophylaxis andtreatment of migraine (Scrip Report; “Migraine—Current trends inresearch and treatment”; PJB Publications Ltd.; May 1991) and in thetreatment of anxiety (Colpart et al. Psychopharmacology 1985, 86,303-305 and Perregaard et al. Current Opinion in Therapeutic Patents1993, 1, 101-128).

[0022] Some clinical studies implicate the 5-HT₂ receptor subtype inaggressive behaviour. Further, atypical serotonin-dopamine antagonistneuroleptics have 5-HT₂ receptor antagonistic effect in addition totheir dopamine blocking properties and have been reported to possessanti-aggressive behaviour (Connor et al. Exp. Opin. Ther. Patents. 1998,8(4), 350-351).

[0023] Recently, evidence has also accumulated which support therationale for selective 5-HT_(2A) antagonists as drugs capable oftreating positive symptoms of psychosis (Leysen et al. CurrentPharmaceutical Design 1997, 3, 367-390 and Carlsson Current Opinion inCPNS Investigational Drugs 2000, 2(1), 22-24).

[0024] Compounds which are 5-HT reuptake inhibitors are well-knownantidepressant drugs.

[0025] 5-HT_(2C) ligands have been found to augment the effect of 5-HTreuptake inhibitors in microdialysis experiments and animal models, andcompounds having 5-HT reuptake inhibiting effect combined with affinityfor the 5-HT_(2C) receptor may therefore be particularly useful for thetreatment of depression and other disorders responsive to serotoninreuptake inhibitors (PCT application No. PCT/DK00/00671).

[0026] Accordingly, dopamine D₄ receptor ligands are potential drugs forthe treatment of schizophrenia and other psychoses, and compounds withcombined effects at the 5-HT transporter may have the further benefit ofimproved effect on depressive and negative symptoms in schizophrenicpatients. Compounds with combined effect at the dopamine D₄ receptor andthe 5-HT_(2A) receptor may have the benefit of improved effect onpositive and negative symptoms of schizophrenia, and the benefit ofeffect on depressive and anxiety symptoms. Furthermore, dopamine D₃antagonistic properties of an antipsychotic drug may reduce the negativesymptoms and cognitive deficits of schizophrenia and result in animproved side effect profile.

SUMMARY OF THE INVENTION

[0027] The object of the present invention is to provide compounds thatare partial agonists or antagonists at the dopamine D₄ receptor and suchcompounds with combined effects at the dopamine D₄ receptor, the D₃receptor, the 5-HT_(2A) receptor, the 5-HT_(2C) receptor and/or the 5-HTtransporter.

[0028] A further object of the present invention is to provide compoundswith such activities which have improved solubility compared to priorart compounds.

[0029] Accordingly, the present invention relates to novel compounds offormula I

[0030] wherein

[0031] (a) one of Y¹ and Y² is N, which is bound to Y⁴, and the other ofY¹ and Y² is CO, CS, SO, or SO₂ and Y⁴is CH₂;

[0032] (b) one of Y¹ and Y² is N, which is bound to Y⁴, and the other ofY¹ and Y² is CH₂ and Y⁴ is CO, CS, SO or SO₂; or

[0033] (c) one of Y¹ and Y² is N, which is bound to Y⁴, and the other ofY¹ and Y² is CH₂ and Y⁴ is CH₂;

[0034] Y³is Z—CH₂, CH₂—Z or CH₂CH₂, and Z is O or S; provided that whenY¹ is N, Y³ may not be Z—CH₂;

[0035] W is a bond or an O, S, CO, CS, SO or SO₂ group;

[0036] n is 0-5, m is 0-5 and m+n is 1-10; provided that when W is O orS, then n≧2 and m≧1; when W is CO, CS, SO or SO₂, then n≧1 and m≧1;

[0037] X is C, CH or N; provided that when X is C, the dotted lineindicates a bond, and when X is N or CH, the dotted line is not a bond;

[0038] R¹-R⁹ are independently selected from hydrogen, halogen, cyano,nitro, amino, hydroxy, C₁₋₆-alkyl-amino, di-C₁₋₆-alkyl-amino,C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio,C₁₋₆-alkyl substituted with hydroxy or thiol, C₃₋₈-cycloalkyl,C₃₋₈-cycloalkyl-C₁₋₆-alkyl, acyl, thioacyl, aryl, trifluoromethyl,trifluoromethylsulfonyl, and C₁₋₆ alkylsulfonyl;

[0039] R¹⁰ is hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₁₋₆-alkyl substituted with hydroxy or thiol, C₃₋₈-cycloalkyl,C₃₋₈-cycloalkyl-C₁₋₆-alkyl, aryl, aryl-C₁₋₆-alkyl, acyl, thioacyl,C₁₋₆-alkylsulfonyl, trifluoromethylsulfonyl or arylsulfonyl or apharmaceutically acceptable acid addition salt thereof.

[0040] In a first particular embodiment of the invention, the indole isbound to X via position 3 of the indole.

[0041] In a second embodiment of the invention, one of Y¹ and Y² is Nwhich is bound to Y⁴ and the other of Y¹ and Y² is CO, and Y⁴ is CH₂.

[0042] In a third embodiment of the invention, one of Y¹ and Y² is N,which is bound to Y⁴, and the other of Y¹ and Y² is CH₂ and Y⁴ is CO.

[0043] In a fourth embodiment of the invention, Y¹ is a nitrogen boundto Y⁴ and one of Y⁴ and Y² is CO and the other is CH₂.

[0044] In a fifth embodiment of the invention, Y¹ is a nitrogen bound toY⁴, Y² is CO and Y⁴ is CH₂.

[0045] In a sixth embodiment of the invention, Y¹ is a nitrogen bound toY⁴, Y² is CH₂ and Y⁴ is CO.

[0046] In a seventh embodiment of the invention, Y² is a nitrogen boundto Y⁴ and one of Y¹ and Y⁴is CO and the other is CH₂.

[0047] In an eighth embodiment of the invention, Y² is a nitrogen atombound to Y⁴, Y¹ is CH₂ and Y⁴ is CO.

[0048] In a ninth embodiment of the invention, Y² is a nitrogen atombound to Y⁴, Y¹ is CO and Y⁴ is CH₂.

[0049] In a tenth embodiment of the invention, one of Y¹ and Y²is N,which is bound to Y⁴, and the other of Y¹ and Y² is CH₂ and Y⁴is CH₂.Such compounds are preferably in the form of pharmaceutically acceptabledi-salts thereof.

[0050] In a further embodiment of the invention, Y³ is CH₂CH₂ or CH₂Z.

[0051] In still further embodiments of the invention, X is C, X is N orX is CH.

[0052] The substituents R¹-R⁹ are in particular selected from hydrogen,halogen, cyano, nitro, amino, C₁₋₆-alkylamino, di-C₁₋₆-alkylamino,C₁₋₆-alkyl, C₃₋₈-cycloalkyl and trifluoromethyl, and R¹⁰ is hydrogen,C₁₋₆-alkyl or acyl and/or W is a bond and n+m is 1 to 6, in particular 3to 6.

[0053] The compounds of the invention are partial agonists or antagonistat the dopamine D₄ receptor. Many compounds have combined effect at thedopamine D₄ receptor and dopamine D₃ receptor affinity, 5-HT_(2A)receptor affinity, 5-HT_(2C) receptor affinity and/or 5-HT reuptakeinhibiting effect.

[0054] Accordingly, the compounds of the invention are considered usefulin the treatment of positive and negative symptoms of schizophrenia,other psychoses, anxiety disorders, such as generalised anxietydisorder, panic disorder, and obsessive compulsive disorder, depression,aggression, side effects induced by conventional antipsychotic agents,migraine, cognitive disorders, ADHD and in the improvement of sleep.

[0055] In another aspect, the present invention provides apharmaceutical composition comprising at least one compound of Formula Ias defined above or a pharmaceutically acceptable acid addition saltthereof in a therapeutically effective amount and in combination withone or more pharmaceutically acceptable carriers or diluents.

[0056] In a further aspect, the present invention provides the use of acompound of Formula I as defined above or an acid addition salt thereoffor the manufacture of a pharmaceutical preparation for the treatment ofthe above mentioned disorders.

DETAILED DESCRIPTION OF THE INVENTION

[0057] The compounds of general Formula I may exist as optical isomersthereof and such optical isomers are also embraced by the invention.

[0058] The term C₁₋₆-alkyl refers to a branched or unbranched alkylgroup having from one to six carbon atoms inclusive, such as methyl,ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl,2-methyl-1-propyl, pentyl and hexyl.

[0059] Similarly, C₂₋₆-alkenyl and C₂₋₆-alkynyl, respectively, designatesuch groups having from two to six carbon atoms, including one doublebond and triple bond respectively, such as ethenyl, propenyl, butenyl,ethynyl, propynyl and butynyl.

[0060] The terms C₁₋₆-alkoxy, C₁₋₆-alkylthio, C₁₋₆-alkylsulfonyl,C₁₋₆-alkylamino, C₁₋₆-alkylcarbonyl, and the like, designate such groupsin which the alkyl group is C₁₋₆ alkyl as defined above.

[0061] The term C₃₋₈-cycloalkyl designates a monocyclic or bicycliccarbocycle having three to eight C-atoms, such as cyclopropyl,cyclopentyl, cyclohexyl, etc.

[0062] The term aryl refers to a carbocyclic aromatic group, such asphenyl, naphthyl, in particular phenyl, including methyl substitutedphenyl, or naphthyl.

[0063] Halogen means fluoro, chloro, bromo or iodo.

[0064] As used herein the term acyl refers to a formyl,C₁₋₆-alkylcarbonyl, arylcarbonyl, aryl-C₁₋₆-alkylcarbonyl,C₃₋₈-cycloalkylcarbonyl or a C₃₋₈-cycloalkyl-C₁₋₆-alkyl-carbonyl groupand the term thioacyl is the corresponding acyl group in which thecarbonyl group is replaced with a thiocarbonyl group.

[0065] The acid addition salts of the compounds of the invention arepharmaceutically acceptable salts formed with non-toxic acids. Exemplaryof such organic salts are those with maleic, fumaric, benzoic, ascorbic,succinic, oxalic, bis-methylenesalicylic, methanesulfonic,ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric,gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic,stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic,benzenesulfonic and theophylline acetic acids, as well as the8-halotheophyllines, for example 8-bromotheophylline. Exemplary of suchinorganic salts are those with hydrochloric, hydrobromic, sulfuric,sulfamic, phosphoric and nitric acids.

[0066] The pharmaceutical compositions of this invention or those whichare manufactured in accordance with this invention may be administeredby any suitable route, for example orally in the form of tablets,capsules, powders, syrups, etc., or parenterally in the form ofsolutions for injection. For preparing such compositions, methods wellknown in the art may be used, and any pharmaceutically acceptablecarriers, diluents, excipients, or other additives normally used in theart may be used.

[0067] Conveniently, the compounds of the invention are administered inunit dosage form containing said compounds in an amount of about 0.01 to100 mg.

[0068] The total daily dose is usually in the range of about 0.05-500mg, and most preferably about 0.1 to 50 mg of the active compound of theinvention.

[0069] The compounds of the invention may be prepared as follows:

[0070] 1) Alkylating a piperazine, piperidine or tetrahydropyridine offormula II with an alkylating derivative of formula III:

[0071] wherein R¹-R¹⁰, X, Y¹, Y², Y³, Y⁴l W, n, m and the dotted lineare as previously defined, and L is a leaving group such as e.g.halogen, mesylate or tosylate;

[0072] 2) Reductive alkylation of an amine of formula II with a reagentof formula IV:

[0073] wherein R¹-R¹⁰, X, Y¹, Y², Y³, Y⁴, W, n, m and the dotted lineare as previously defined and E is an aldehyde or an activatedcarboxylic acid group;

[0074] 3) Alkylating a compound of formula V with an alkylatingderivative of formula VI:

[0075] wherein R¹-R¹⁰, X, Y³, W, n, m and the dotted line are aspreviously defined, one of Y⁵ and Y⁶ is NH or N⁻and the other of Y⁵ andY⁶ is CO, CS, SO, SO₂ or CH₂ and L is a leaving group such as e.g.halogen, mesylate or tosylate; or

[0076] 4) Reducing the double bond in the tetrahydropyridinyl ring inderivatives of the following formula VII:

[0077] wherein R¹-R¹⁰, Y¹, Y², Y³, Y⁴, W, m and n are as previouslydefined;

[0078] 5) Reducing the amide carbonyl in a compound of formula VIII:

[0079] wherein R¹-R¹⁰, Y¹, Y², Y³, Y⁴, n, m, W and the dotted line areas previously defined;

[0080] 6) Reducing the amide group compounds of formula IX:

[0081] wherein R¹-R¹⁰, X, Y¹, Y², Y³, n, m, W and the dotted line are aspreviously defined;

[0082] 7) Reductive alkylation of a derivative of formula Va with anacylating derivative of formula X:

[0083] wherein R¹-R¹⁰, X, Y³, W, n, m and the dotted line are aspreviously defined, one of Y⁷ and Y⁸ is NH and the other of Y⁷ and Y⁸ isCH₂ and E is an aldehyde or an activated carboxylic acid;

[0084] 8) Acylation of an amine of formula Va with a reagent of formulaX:

[0085] wherein R¹-R¹⁰, X, Y³, W, n, m and the dotted line are aspreviously defined, one of Y⁷ and Y⁸ is NH and the other of Y⁷ and Y⁸ isCH₂ and E is an aldehyde or an activated carboxylic acid;

[0086] 9) Cleaving a polymer bound derivative of formula XI

[0087] wherein R¹-R⁹, Y¹, Y², Y³, X, W, m and n are as previouslydefined and R′OH is hydroxyethyl or hydroxymethyl polystyrene, Wangresin or analogous polyethylene glycol polystyrene resins; whereupon thecompound of Formula I is isolated as the free base or a pharmaceuticallyacceptable acid addition salt thereof.

[0088] The alkylation according to method 1) and 3) is convenientlyperformed in an inert organic solvent such as a suitably boiling alcoholor ketone, preferably in the presence of an organic or inorganic base(potassium carbonate, diisopropylethylamine or triethylamine) at refluxtemperature. Alternatively, the alkylation can be performed at a fixedtemperature, which is different from the boiling point, in one of theabove-mentioned solvents or in dimethyl formamide (DMF),dimethylsulfoxide (DMSO) or N-methylpyrrolidin-2-one (NMP), preferablyin the presence of a base.

[0089] The synthesis the amines of formula (II),3-(piperidin-4-yl)-1H-indoles and3-(3,6-dihydro-2H-pyridin-4-yl)-1H-indoles has been described in theliterature (see e.g. EP-A1-465398). Alkylating reagents of formula (III)are known from the literature (see Oshiro et al. J. Med. Chem. 2000, 43,177-189 and EP-B1-512525), or they can be prepared by methods obvious toa chemist skilled in the art (see e.g. Kowalski et al. J. HeterocyclicChem. 2000, 37, 187-189, Mokrosz et al. Pharmazie 1997, 52, 423-428 andMisztal et al. Med. Chem. Res. 1992, 2, 82-87). Alkylating reagents offormula (VI) can be prepared by methods obvious to a chemist skilled inthe art, and amines of formula (V) are commercially available ordescribed in the literature.

[0090] The reductive alkylation according to methods 2) and 7) isperformed by standard literature methods. The reaction can be performedin two steps, e.g. coupling of derivatives of formula II/Va and thereagent of formula IV/X by standard methods via the carboxylic acidchloride or by use of coupling reagents such as e.g. dicyclohexylcarbodiimide followed by reduction of the resulting amide with lithiumaluminium hydride or alane. The reaction can also be performed by astandard one-pot procedure. Carboxylic acids or aldehydes of formulaIV/X can be prepared by methods obvious to a chemist skilled in the art.

[0091] The alkylation according to method 3) is conveniently performedas described above or by reacting the nitrogen anion of V with VI. Thenitrogen anion of V can be prepared in an inert organic solvent, e.g.dimethyl formamide (DMF), dimethylsulfoxide (DMSO) orN-methylpyrrolidin-2-one (NMP), by the use of a strong base, e.g. NaH,before the alkylation.

[0092] The reduction of the double bond according to method 4) isgenerally performed by catalytic hydrogenation at low pressure (<3 atm.)in a Parr apparatus, or by using reducing agents such as diborane orhydroboric derivatives as produced in situ from NaBH₄ in trifluoroaceticacid in inert solvents such as tetrahydrofuran (THF), dioxane or diethylether. Starting materials of formula (VII) may be prepared by methods1), 3), 7) and 8).

[0093] Reduction of amide groups according to methods 5) and 6) is mostconveniently performed with lithium aluminium hydride or alane in aninert organic solvent such as e.g. tetrahydrofuran (THF) or diethyletherfrom 0° C. to reflux temperature. Starting materials of formula (VIII)may be prepared by methods 2) and 3), whereas starting materials offormula (IX) may be prepared by methods 1), 7) and 8).

[0094] The coupling according to method 8) is conveniently performed bythe use of coupling reagents such as e.g. dicyclohexyl carbodiimide.

[0095] The derivatives of structure (XI) is prepared by means of a solidphase synthesis sequence as outlined in Scheme 1 below. The firstbuilding block (XII), prepared by methods obvious to the chemist skilledin the art, is generally attached to the resin (polystyrene bound ethyl4-nitrophenyl carbonate) using base e.g. N,N-dimethylaminopyridine andN,N-diisopropylethylamine at elevated temperature (e.g. 50-100° C.) inan aprotic solvent (e.g. DMF or DMSO) to yield (XIII). Afterdeprotection of the amino group by trifluoroacetic acid (resin XIV), thesecond diversifying building block was introduced by alkylation. Thealkylation was performed at elevated temperature (50-100° C.) in anaprotic solvent such as DMF, acetone or acetonitrile leading to resin(XV). After deprotection of the carboxylic acid ester by lotrifluoroacetic acid (resin XVI), the third diversifying building blockof formula (Va) was introduced by standard amide forming reactionsequence, e.g. converting the carboxylic acid to the corresponding acidchloride using thionyl chloride at low temperature in dichloromethane,acetonitrile or DMF followed by treatment with an amine. The finalproduct was cleaved from the resin using diluted sodium methoxide in amethanol/tetrahydrofuran mixture at ambient temperature.

[0096] Experimental Section

[0097] Melting points were determined on a Büchi B-540 apparatus and areuncorrected. Mass spectra were obtained on a Quattro MS-MS system fromVG Biotech, Fisons Instruments. Analytical LC-MS data were obtained on aPE Sciex API 150EX instrument equipped with IonSpray source and ShimadzuLC-8A/SLC-10A LC system. The LC conditions (50×4.6 mm YMC ODS-A with 5μm particle size) were linear gradient elution withwater/acetonitrile/trifluoroacetic acid (90:10:0.05) towater/acetonitrile/trifluoroacetic acid (10:90:0.03) in 7 min at 2mL/min. Purity was determined by integration of the UV trace (254 nm).The retention times R_(t) are expressed in minutes. PreparativeLC-MS-separation was performed on the same instrument. The LC conditions(50×20 mm YMC ODS-A with 5 μm particle size) were linear gradientelution with water/acetonitrile/trifluoroacetic acid (80:20:0.05) towater/acetonitrile/trifluoroacetic acid (5:95:0.03) in 7 min at 22.7mL/min. Fraction collection was performed by split-flow MS detection. ¹HNMR spectra were recorded at 250.13 MHz on a Bruker AC 250 or at 500.13MHz on a Bruker DRX 500. Deuterated chloroform (99.8% D) ordimethylsulfoxide (99.9% D) were used as solvents. TMS was used asinternal reference standard. Chemical shifts are expressed as ppmvalues. The following abbreviations are used for multiplicity of NMRsignals: s=singlet, d=doublet, t=triplet, q=quartet, qv=quintet,h=heptet, dd=double doublet, dt=double triplet, dq=double quartet,tt=triplet of triplets, m=multiplet, b=broad. NMR signals correspondingto acidic protons are to some extent omitted. Content of water incrystalline compounds was determined by Karl Fischer titration. Forcolumn chromatography, silica gel of type Kieselgel 60, 40-60 mesh ASTMwas used. For ion-exchange chromatography, the following material wasused: SCX-columns (1 g) from Varian Mega Bond Elut®, Chrompack cat. No.220776. Prior to use, the SCX-columns were pre-conditioned with 10%solution of acetic acid in methanol (3 mL).

EXAMPLES

[0098] Preparation of Intermediates

[0099] A. Alkylating Reagents

[0100] 1-(2-Chloroethyl)-3,4-dihydroquinolin-2(1H)-one

[0101] A suspension of sodium hydride (3.0 g, 60% in mineral oil) anddimethyl formamide (100 mL) was kept at 15-18° C. followed by theaddition of a solution of 3,4-dihydroquinolin-2(1H)-one (10.0 g) indimethyl formamide (150 mL). The resulting mixture was stirred at roomtemperature for 60 min followed by the addition of a solution of2-chloroethyl acetate (10.0 g) in dimethyl formamide (50 mL) at atemperature of 20° C. The resulting mixture was heated at 80° C. for 2½h, cooled and poured onto ice. The aqueous phase was extracted withethyl acetate, and the combined organic phases were washed with brine,dried (MgSO₄) and concentrated in vacuo. The crude product was purifiedby flash chromatography on silicagel (eluent: ethyl acetate/heptane 1:1)to give crude 1-(2-acetoxyethyl)-3,4-dihydroquinolin-2(1H)-one (10.2 g).A mixture of crude 1-(2-acetoxyethyl)-3,4-dihydroquinolin-2(1H)-one,sodium methanolate (2.5 mL, 30% in methanol) and methanol (250 mL) wasstirred at room temperature for 16 h and subsequently concentrated invacuo. The residue was purified by flash chromatography on silicagel(eluent: ethyl acetate/heptane 1:1) to give the corresponding alcohol asa red crystalline compound (4.9 g). This alcohol was dissolved intetrahydrofuran (100 mL) followed by the addition of triethylamine (8.2mL). The resulting mixture was cooled to 5-6° C. followed by theaddition of a solution of methane sulfonic acid chloride (2 mL) intetrahydrofuran (25 mL). The mixture was filtered and evaporated todryness in vacuo. The residue was dissolved in dimethyl formamide (50mL) followed by addition of lithium chloride (4.9 g), and the resultingmixture was heated at 70° C. for 5 min. The mixture was poured ontobrine, and the aqueous phase was extracted with ethyl acetate. Thecombined organic phases were dried (MgSO₄), filtered and concentrated invacuo. The residue was purified by flash chromatography on silicagel(eluent:ethyl acetate/heptane 1:1) to give the product as a red oil (2.9g).

[0102] 1-(3-Bromopropan-1-yl)-3,4-dihydroquinolin-2(1H)-one

[0103] A suspension of sodium hydride (6.8 g, 60% in mineral oil) anddimethyl formamide (200 mL) was kept at 20-25° C. followed by theaddition of a solution of 3,4-dihydroquinolin-2(1H)-one (25.0 g) indimethyl formamide (180 mL). The resulting mixture was stirred at roomtemperature for 10 min followed by the addition of a solution of1,3-dibromopropane (172 g) in dimethyl formamide (150 mL) at atemperature of 20-35° C. The resulting mixture was stirred at 30° C. for20 min and concentrated in vacuo. The residue was poured onto ice, andthe aqueous phase was extracted with ethyl acetate. The combined organicphases were washed with brine, dried (MgSO₄) and concentrated in vacuo.The crude product was purified by flash chromatography on silicagel(eluent:ethyl acetate/heptane 1:1) to give the product as a yellow oil(27 g).

[0104] The following compounds were prepared in a similar manner

[0105] 1-(4-Bromobutan-1-yl)-3,4-dihydroquinolin-2(1H)-one

[0106] from 3,4-dihydroquinolin-2(1H)-one and 1,4-dibromobutane

[0107] 1-(5-Bromopentan-1-yl)-3,4-dihydroquinolin-2(1H)-one

[0108] from 3,4-dihydroquinolin-2(1H)-one and 1,5-dibromopentane

[0109] 4-(4-Bromobutan-1-yl)-3,4-dihydro-2H-1,4-benzoxazin-3(4H)-one

[0110] from 3,4-dihydro-2H-1,4-benzoxazin-3(4H)-one and1,4-dibromobutane

[0111] 2-(3-Hydroxypropan-1-yl)-3,4-dihydroisoquinolin-1(2H)-one

[0112] from 3,4-dihydroisoquinolin-1(2H)-one and 3-bromopropanol

[0113] 2-(4-Bromobutan-1-yl)-3,4-dihydroisoquinolin-1(2H)-one

[0114] from 3,4-dihydroisoquinolin-1(2H)-one and 1,4-dibromobutane

[0115] 1-(3-Bromopropan-1-yl)-3,4-dihydroisoquinolin-1(2H)-one

[0116] The compound2-(3-hydroxypropan-1-yl)-3,4-dihydroisoquinolin-1(2H)-one was dissolvedin tetrahydrofuran (100 mL) followed by the addition of triethylamine(5.2 mL). The resulting mixture was cooled to 6-11° C. followed by theaddition of a solution of methane sulfonic acid chloride (1.4 mL) intetrahydrofuran (25 mL). The mixture was stirred at 5 ° C. for 10 min,filtered and concentrated in vacuo. The residue was dissolved in acetone(250 mL) followed by addition of lithium bromide (6.5 g), and theresulting mixture was boiled under reflux for 2 h. The mixture waspoured onto brine, and the aqueous phase was extracted with ethylacetate. The combined organic phases were dried (MgSO₄), filtered andconcentrated in vacuo. The residue was purified by flash chromatographyon silicagel (eluent:ethyl acetate/heptane 1:2) to give the product as ayellow oil (2.7 g).

[0117] 3-Chloro-1-(3,4-dihydro-1H-isoquinolin-2-yl)propan-1-one

[0118] A solution of 3-chloropropanoyl chloride (10.5 g) intetrahydrofuran (400 mL) was cooled down to 6° C. followed by theaddition of a solution of 3,4-dihydro-1H-isoquinoline (10.0 g). Theresulting mixture was stirred at 10° C. for 30 min, filtered andconcentrated in vacuo. The residue was subjected to a standard aqueouswork up procedure followed by purification by flash chromatography onsilicagel (eluent:ethyl acetate/heptane 1:1) to give the product as acolourless oil (10 g).

[0119] The following compounds were prepared in a similar manner

[0120] 3-Bromo-1-(3,4-dihydro-1H-isoquinolin-2-yl)propan-1-one

[0121] from 3,4-dihydro-1H-isoquinoline and 3-bromopropanoyl chloride

[0122] 4-Chloro-1-(3,4-dihydro-1H-isoquinolin-2-yl)butan-1-one

[0123] from 3,4-dihydro-1H-isoquinoline and 4-chlorobutanoyl chloride

[0124] 4-Chloro-1-(3,4-dihydro-2H-quinolin-1-yl)butan-1-one

[0125] from 3,4-dihydro-2H-quinoline and 4-chlorobutanoyl chloride

[0126] Preparation of Solid Supported Intermediates

[0127] Preparation of 4-nitrophenyloxycarbonyloxyethyl polystyrene

[0128] A 2 L round bottom flask was charged with hydroxyethylpolystyrene (62.9 g, 83 mmol, commercially available from Rapp Polymere,cat. no. HA 1 400 00), N-methyl-morpholine (20 mL, 183 mmol) and drydichloromethane (900 mL). The suspension was cooled on an ice bath and4-nitrophenyl chloroformiate dissolved in dry dichloromethane (400 mL)was added during 5 minutes. The mixture was stirred at room temperaturefor 16 h. The resin was filtered off and washed with dry dichloromethane(5×200 mL). The resin was dried in vacuo (20° C., 72 h) to yield thetitle resin (79.6 g).

[0129] Preparation of Polymer Bound7-chloro-3-(piperidin-4-yl)-1H-indole

[0130] A 100 mL round bottom flask was charged with4-nitrophenyloxycarbonyloxyethyl polystyrene (4.0 g, 4.3 mmol),7-chloro-3-(1-tert-butoxycarbonylpiperidin-4-yl)-1H-indole (2.7 g, 8.1mmol), diisopropylethylamine (3.5 mL, 20.2 mmol),4-dimethylaminopyridine (0.5 g, 4 mmol) and dry dimethyl formamide (50mL). The mixture was stirred at 90° C. for 72 h. After cooling to roomtemperature, the resin was filtered off and washed with dry dimethylformamide (3×25 mL), dry acetonitrile (3×25 mL) and dry dichloromethane(3×25 mL). The resin was transferred to a 250 mL glass cylinder with afritte and a three way junction in the bottom. The resin was thentreated for 20 minutes with 60 mL of a 1:1 mixture of dichloromethaneand trifluoroacetic acid containing anisole (2%, w/w) and methionine(0.2 %, w/w), using a flow of nitrogen to agitate the resin (Caution:Generation of carbon dioxide). The resin was filtered off and washedwith dry dichloromethane (25 mL), a 1:1 mixture ofdichloromethane:triethylamine (3×25 mL) and dry dichloromethane (3×25mL). The resin was dried in vacuo (20° C., 20 h) to yield the titleresin (3.8 g).

[0131] The following polymer bound compounds were prepared in a similarmanner

[0132] 4-Chloro-3-(piperidin-4-yl)-1H-indole

[0133] 4-Fluoro-3-(piperidin-4-yl)-1H-indole

[0134] 5-Chloro-3-(piperidin-4-yl)-1H-indole

[0135] 5-Fluoro-3-(piperidin-4-yl)-1H-indole

[0136] 6-Chloro-3-(piperidin-4-yl)-1H-indole

[0137] Preparation of Polymer Bound3-[4-(7-chloro-1H-indol-3-yl)piperidin-1-yl]propionic acid

[0138] A 25 mL round bottom flask was charged with polymer bound7-chloro-3-(piperidin-4-yl)-1H-indole (1.0 g, 0.98 mmol), triethylamine(80.2 mL), tert-butyl 3-bromopropionate and dry acetonitrile (5 mL). Themixture was stirred at 80° C. for 3 h. After cooling to roomtemperature, the resin was filtered off and washed with dry acetonitrile(3×10 mL) and dry dichloromethane (3×10 mL). The resin was treated for20 minutes with 8 mL of a 1:1 mixture of dichloromethane andtrifluoroacetic acid containing anisole (2%, w/w) and methionine (0.2%,w/w) (Caution: Generation of carbon dioxide). The resin was filtered offand washed with dry dichloromethane (10 mL), a 1:1 mixture ofdichloromethane:triethylamine (3×10 mL) and dry dichloromethane (3×10mL). The resin was dried in vacuo (20° C., 20 h) to yield the titleresin (1.0 g).

[0139] The following polymer bound compounds were prepared in a similarmanner

[0140] 3-[4-(4-Chloro-1H-indol-3-yl)piperidin-1-yl]propionic acid

[0141] 3-[4-(4-Fluoro-1H-indol-3-yl)piperidin-1-yl]propionic acid

[0142] 3-[4-(5-Fluoro-1H-indol-3-yl)piperidin-1-yl]propionic acid

[0143] 3-[4-(6-Chloro-1H-indol-3-yl)piperidin-1-yl]propionic acid

[0144] 4-[4-(4-Chloro-1H-indol-3-yl)piperidin-1-yl]butyric acid

[0145] 4-[4-(4-Fluoro-1H-indol-3-yl)piperidin-1-yl]butyric acid

[0146] 4-[4-(5-Chloro-1H-indol-3-yl)piperidin-1-yl]butyric acid

[0147] 4-[4-(5-Fluoro-1H-indol-3-yl)piperidin-1-yl]butyric acid

[0148] 4-[4-(7-Chloro-1H-indol-3-yl)piperidin-1-yl]butyric acid

[0149] 5-[4-(4-Chloro-1H-indol-3-yl)piperidin-1-yl]pentanoic acid

[0150] 5-[4-(5-Fluoro-1H-indol-3-yl)piperidin-1-yl]pentanoic acid

[0151] 5-[4-(7-Chloro-1H-indol-3-yl)piperidin-1-yl]pentanoic acid

[0152] 6-[4-(4-Fluoro-1H-indol-3-yl)piperidin-1-yl]hexanoic acid

[0153] 6-[4-(4-Chloro-1H-indol-3-yl)piperidin-1-yl]hexanoic acid

[0154] 6-[4-(5-Fluoro-1H-indol-3-yl)piperidin-1-yl]hexanoic acid

[0155] 6-[4-(6-Chloro-1H-indol-3-yl)piperidin-1-yl]hexanoic acid

[0156] 6-[4-(7-Chloro-1H-indol-3-yl)piperidin-1-yl]hexanoic acid

[0157] Preparation of the Compounds of the Invention

Example 1

[0158] 1a,5-Fluoro-3-{1-[2-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)ethyl]piperidin-4-yl}-1H-indolehydrochloride

[0159] A mixture of 5-fluoro-3-(piperidin-4-yl)-1H-indole (0.3 g),1-(2-chloroethyl)-3,4-dihydroquinolin-2(1H)-one (0.41 g) andtriethylamine (0.75 g) in dimethyl formamide (5 mL) and butanone (10 mL)was boiled under reflux for 6 h. The mixture was concentrated in vacuo,and the residue was purified by flash chromatography on silicagel(eluent:ethyl acetate/ethanol/triethylamine 90:10:5) to give the crudeproduct, which was isolated as the hydrochloride salt from acetone as awhite crystalline compound (0.04 g). ¹H NMR (DMSO-d₆): 2.00-2.25 (m,4H); 2.60 (t, 2H); 2.90 (t, 2H); 2.95-3.10 (m, 1H); 3.10-3.30 (m, 4H);3.70 (d, 2H); 4.35 (t, 2H); 6.90 (t, 1H); 7.05 (t, 1H); 7.15-7.40 (m,5H); 7.50 (d, 1H); 10.95 (broad s, 1H); 11.05 (s, 1H). MS m/z: 392(MH+), 174.

[0160] The following compounds were prepared in a similar manner

[0161] 1b,5-Fluoro-3-{1-[3-(1-oxo-3,4-dihydro-1H-quinolin-2-yl)propan-1-yl]piperidin-4-yl}-1H-indole,oxalate

[0162] from 5-fluoro-3-(piperidin-4-yl)-1H-indole and1-(3-bromopropan-1-yl)-3,4-dihydroisoquinolin-1(2H)-one. ¹H NMR(DMSO-d₆): 1.90-2.15 (m, 6H); 2.95-3.15 (m, 7H); 3.55-3.60 (m, 6H); 6.90(t, 1H); 7.20 (s, 1H); 7.30 (d, 1H); 7.30-7.40 (m, 4H); 7.45-7.50 (m,1H); 7.90 (d, 1H); 11.05 (s, 1H). MS m/z: 406 (MH+), 188.

[0163] 1c,5-Fluoro-3-{1-[4-(1-oxo-3,4-dihydro-1H-quinolin-2-yl)butan-1-yl]piperidin-4-yl}-1H-indole,hydrochloride

[0164] from 5-fluoro-3-(piperidin-4-yl)-1H-indole and2-(4-bromobutan-1-yl)-3,4-dihydroisoquinolin-1(2H)-one. ¹H NMR(DMSO-d₆): 1.55-1.70 (m, 2H); 1.70-1.85 (m, 2H); 2.05 (d, 2H); 2.10-2.25(m, 2H); 2.90-3.15 (7H); 3.40- 3.65 (m, 6H); 6.90 (t, 1H); 7.20 (s, 1H);7.30 (d, 1H); 7.30-7.40 (m, 2H); 7.40-7.55 (m, 2H); 7.90 (d, 1H); 10.75(broad s, 1H); 11.05 (s, 1H). MS m/z: 420 (MH+).

Example 2

[0165] 2a,5-Fluoro-3-{1-[3-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)propan-1-yl]piperidin-4-yl}-1H-indole,hydrochloride

[0166] A mixture of 5-fluoro-3-(piperidin-4-yl)-1H-indole (5.0 g),1-(3-bromopropan-1-yl)-3,4-dihydroquinolin-2(1H)-one (7.7 g) andpotassium carbonate (7.0 g) in dimethyl formamide (40 mL) was heated at100° C. for 2½ h. The mixture was cooled, filtered and concentrated invacuo. The residue was purified by flash chromatography on silicagel(eluent:ethyl acetate followed by ethyl acetate/ethanol 90:10) to givethe product as an orange oil (9.1 g). The title compound (1.8 g of freebase) was isolated as the hydrochloride salt from tetrahydrofuran as awhite crystalline compound (1.5 g). Mp 210-212° C. ¹H NMR (DMSO-d₆):2.00-2.20 (m, 6H); 2.60 (t, 2H); 2.90 (t, 2H); 2.95-3.10 (m, 3H);3.10-3.20 (m, 2H); 3.55 (d, 2H); 3.95 (t, 2H); 6.90 (t, 1H); 7.05 (t,1H); 7.15-7.30 (m, 4H); 7.30-7.40 (m, 1H); 7.50 (d, 1H); 10.55 (broad s,1H); 11.05 (s, 1H). MS m/z: 406 (MH+).

[0167] The following compounds were prepared in a similar manner

[0168] 2b,5-Fluoro-3-{1-[5-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)pentan-1-yl]piperidin-4-yl}-1H-indole,hydrochloride

[0169] from 5-fluoro-3-(piperidin-4-yl)-1H-indole and1-(5-bromopentan-1-yl)-3,4-dihydroquinolin-2(1H)-one. Mp 199-200° C. ¹HNMR (DMSO-d₆): 1.30-1.40 (m, 2H); 1.55-1.60 (m, 2H); 1.70-1.80 (m, 2H);2.05-2.15 (m, 4H); 2.55 (t, 2H); 2.85 (t, 2H); 2.95-3.10 (m, 5H); 3.55(d, 2H); 3.90 (t, 2H); 6.90 (t, 1H); 7.00 (t, 1H); 7.15 (d, 1H);7.20-7.30 (m, 3H); 7.30-7.35 (m, 1H); 7.50 (d, 1H); 12.20 (broad s, 1H);11.05 (s, 1H). MS m/z: 434 (MH+).

[0170] 2c,5-Chloro-3-{1-[3-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)propan-1-yl]piperidin-4-yl}-1H-indole,hydrochloride

[0171] from 5-chloro-3-(piperidin-4-yl)-1H-indole and1-(3-bromopropan-1-yl)-3,4-dihydroquinolin-2(1H)-one. Mp 142-146° C. ¹HNMR (DMSO-d₆): 1.95-2.15 (m, 6H); 2.60 (t, 2H); 2.90 (t, 2H); 2.95-3.15(3H); 3.15-3.20 (m, 2H); 3.55 (d, 2H); 3.95 (t, 2H); 7.00-7.10 (m, 2H);7.20-7.30 (m, 4H); 7.35 (d, 1H); 7.75 (s, 1H), 11.30 (broad s, 1H);11.15 (s, 1H). MS m/z: 422 (MH+), 188.

[0172] 2d,5-Chloro-3-{1-[4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)butan-1-yl]piperidin-4-yl}-1H-indole,hydrochloride

[0173] from 5-chloro-3-(piperidin-4-yl)-1H-indole and1-(4-bromobutan-1-yl)-3,4-dihydroquinolin-2(1H)-one. Mp 229-231° C. ¹HNMR (DMSO-d₆): 1.55-1.65 (m, 2H); 1.70-1.80 (m, 2H); 2.00-2.15 (m, 4H);2.55 (t, 2H); 2.85 (t, 2H); 2.95-3.15 (m, 5H); 2.55 (d, 2H); 3.95 (t,2H); 7.00 (t, 1H); 7.05 (d, 1H); 7.15 (d, 1H); 7.20-7.30 (m, 3H); 7.40(d, 1H); 7.75 (s, 1H); 10.05 (broad s, 1H); 11.10 (s, 1H). MS m/z: 436(MH+).

[0174] 2e,5-Chloro-3-{1-[5-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)pentan-1-yl]piperidin-4-yl}-1H-indole,hydrochloride

[0175] from 5-chloro-3-(piperidin-4-yl)-1H-indole and1-(5-bromopentan-1-yl)-3,4-dihydroquinolin-2(1H)-one. Mp 206-209° C. ¹HNMR (DMSO-d₆): 1.30-1.40 (m, 2H); 1.55-1.65 (m, 2H); 1.70-1.80 (m, 2H);2.00-2.15 (m, 4H); 2.55 (t, 2H); 2.85 (t, 2H); 2.95-3.10 (m, 4H);3.10-3.25 (m, 1H); 3.55 (d, 2H); 3.90 (t, 2H); 7.00 (t, 1H); 7.05 (d,1H); 7.15 (d, 1H); 7.20-7.30 (m, 3H); 7.40 (d, 1H); 7.75 (s, 1H); 11.20(broad s, 1H); 11.15 (s, 1H). MS m/z: 450 (MH+), 299.

[0176] 2f,7-Chloro-3-{1-[4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)butan-1-yl]piperidin-4-yl}-1H-indole,hydrochloride

[0177] from 7-chloro-3-(piperidin-4-yl)-1H-indole and1-(4-bromobutan-1-yl)-3,4-dihydroquinolin-2(1H)-one. Mp 253-254° C. ¹HNMR (DMSO-d₆): 1.55-1.65 (m, 2H); 1.75-1.85 (m, 2H); 2.05-2.25 (m, 4H);2.55 (t, 2H); 2.90 (t, 2H); 2.95-3.15 (m, 5H); 3.55 (d, 2H); 3.95 (t,2H); 6.95-7.05 (m, 2H); 7.15-7.30 (m, 5H); 7.70 (d, 1H); 10.60 (broad s,1H); 11.30 (s, 1H). MS m/z: 436 (MH+), 289.

[0178] 2g,5-Fluoro-3-{1-[4-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl)butan-1-yl]piperidin-4-yl}-1H-indole,hydrochloride

[0179] from 5-fluoro-3-(piperidin-4-yl)-1H-indole and4-(4-bromobutan-1-yl)-3,4-dihydro-2H-1,4-benzoxazin-3(4H)-one. Mp 83-92°C. ¹H NMR (DMSO-d₆): 1.60-1.70 (m, 2H); 1.75-1.85 (m, 2H); 2.00-2.20 (m,4H); 2.95-3.15 (m, 5H); 3.55 (d, 2H); 3.95 (t, 2H); 4.65 (s, 2H); 6.90(t, 1H); 7.00-7.05 (m, 2H); 7.05-7.15 (m, 1H); 7.20 (s, 1H); 7.25 (d,1H); 7.30-7.40 (m, 1H); 7.50 (d, 1H); 10.45 (broad s, 1H); 11.05 (s,1H). MS m/z: 422 (MH+), 273.

[0180] 2h,5-Chloro-3-{1-[4-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl)butan-1-yl]piperidin-4-yl}-1H-indole,hydrochloride

[0181] from 5-chloro-3-(piperidin-4-yl)-1H-indole and4-(4-bromobutan-1-yl)-3,4-dihydro-2H-1,4-benzoxazin-3(4H)-one. Mp222-224° C. ¹H NMR (DMSO-d₆): 1.60-1.70 (m, 2H); 1.75-1.85 (m, 2H);2.05-2.15 (m, 4H); 3.00-3.15 (m, 5H); 3.55 (d, 2H); 3.95 (t, 2H); 4.65(s, 2H); 7.00-7.10 (m, 4H); 7.20 (s, 1H); 7.25 (d, 1H); 7.40 (d, 1H);7.75 (s, 1H); 10.30 (broad s, 1H); 11.15 (s, 1H). MS m/z: 438 (MH+),291, 204.

Example 3

[0182] 3a,5-Fluoro-3-{1-[3-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)propan-1-yl]-3,6-dihydro-2H-pyridin-4-yl}-1H-indole,oxalate

[0183] A mixture of 5-fluoro-3-(3,6-dihydro-2H-pyridin-4-yl)-1H-indole(3.0 g) and potassium carbonate (6.2 g) in butanone (250 mL) was heateduntil reflux temperature followed by the addition of1-(3-bromopropan-1-yl)-3,4-dihydroquinolin-2(1H)-one (5.0 g) in butanone(50 mL). The resulting mixture was boiled under reflux for 10 h,filtered and concentrated in vacuo (7.7 g). The residue was purified byflash chromatography on silicagel (eluent:ethyl acetate/triethylamine100:5) to give the crude product, which was crystallized fromtetrahydrofuran/ethyl acetate. The title compound was isolated as theoxalate salt from acetone/tetrahydrofuran as a yellowish crystallinecompound (1.7 g). Mp 203-206° C. ¹H NMR (DMSO-d₆): 1.95-2.05 (m, 2H);2.55 (t, 2H); 2.75 (s, 2H); 2.85 (t, 2H); 3.15 (t, 2H); 3.35 (s, 2H);3.80 (s, 2H); 3.95 (t, 2H); 6.05 (s, 1H); 6.95-7.05 (m, 2H); 7.15-7.30(m, 3 H); 7.35-7.45 (m, 1H); 7.50-7.60 (m, 2H); 11.50 (s, 1H). MS m/z:404 (MH+), 218.

[0184] The following compounds were prepared in a similar manner

[0185] 3b,5-Fluoro-3-{1-[4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)butan-1-yl]-3,6-dihydro-2H-pyridin-4-yl}-1H-indole,hydrochloride

[0186] from 5-fluoro-3-(3,6-dihydro-2H-pyridin-4-yl)-1H-indole and1-(4-bromobutan-1-yl)-3,4-dihydroquinolin-2(1H)-one. Mp 124-125° C. ¹HNMR (DMSO-d₆): 1.55-1.65 (m, 2H); 1.80 (q, 2H); 2.55 (t, 2H); 2.75 (d,1H); 2.85-2.95 (m, 3H); 3.15-3.30 (m, 3H); 3.55-3.65 (m, 1H); 3.75 (d,1H); 3.90-4.00 (m, 3H); 6.10 (s, 1H); 6.95-7.05 (m, 2H); 7.15 (d, 1H);7.20-7.30 (m, 2H); 7.40-7.45 (m, 1H); 7.55-7.65 (m, 2H); 10.70 (broad s,1H); 11.50 (s, 1H). MS m/z: 418 (MH+), 231.

[0187] 3c,5-Fluoro-3-{1-[5-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)pentan-1-yl]-3,6-dihydro-2H-pyridin-4-yl}-1H-indole,oxalate

[0188] from 5-fluoro-3-(3,6-dihydro-2H-pyridin-4-yl)-1H-indole and1-(5-bromopentan-1-yl)-3,4-dihydroquinolin-2(1H)-one. Mp 205-207° C. ¹HNMR (DMSO-d₆): 1.35 (t, 2H); 1.55 (t, 2H); 1.75 (t, 2H); 2.55 (t, 2H);2.75 (s, 2H); 2.85 (t, 2H); 3.10 (t, 2H); 3.35 (s, 2H); 3.80 (s, 2H);3.90 (t, 2H); 6.10 (s, 1H); 6.95-7.05 (m, 2H); 7.15 (d, 1H); 7.20-7.30(m, 2H); 7.40-7.45 (m, 1H); 7.55-7.60 (m, 2H); 11.50 (s, 1H). MS m/z:432 (MH+), 245.

Example 4

[0189] 4,5-Fluoro-3-{1-[4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)butan-1-yl]piperidin-4-yl}-1H-indole,hydrochloride

[0190] A mixture of5-fluoro-3-{1-[4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)butan-1-yl]-3,6-dihydro-2H-pyridin-4-yl}-1H-indole(3.5 g), ethanol (100 mL), acetic acid (100 mL) and platinum oxide (0.4g) was shaken under 3 atm for 16 h. The mixture was filtered, evaporatedin vacuo to about a 100 mL, which subsequently was poured onto ice andadded aqueous ammonia to basic pH. The aqueous phase was extracted withethyl acetate, and the combined organic phases were washed with brine,dried (MgSO₄), and concentrated in vacuo. The residue was purified byflash chromatography on silicagel (eluent:ethyl acetate/triethylamine100:4) to give the crude product (2.0 g). The title compound wasisolated as the hydrochloride salt from ethyl acetate as a whitecrystalline compound (2.0 g). Mp 212-213° C. ¹H NMR (DMSO-d₆): 1.55-1.65(m, 2H); 1.75-1.85 (m, 2H); 2.00-2.20 (m, 4H); 2.55 (t, 2H); 2.85 (t,2H); 2.95-3.15 (m, 5H); 3.55 (d, 2H); 3.95 (t, 2H); 6.90 (t, 1H); 7.00(t, 1H); 7.15-7.30 (m, 4H); 7.30-7.40 (m, 1H); 7.50 (d, 1H); 10.55(broad s, 1H); 11.05 (s, 1H). MS m/z: 420 (MH+), 273, 202.

Example 5

[0191] 5a,5-Fluoro-1-methyl-3-{1-[3-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)propan-1-yl]piperidin-4-yl}-1H-indole,oxalate

[0192] A suspension of sodium hydride (0.5 g, 60% in mineral oil) anddimethyl formamide (60 mL) was kept at 22-24° C. followed by theaddition of a solution of5-fluoro-3-{1-[3-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)propan-1-yl]piperidin-4-yl}-1H-indole(4.9 g) in dimethyl formamide (50 mL). The resulting mixture was stirredat room temperature for 25 min followed by the addition of a solution ofmethyl iodide (2.0 g) in dimethyl formamide (15 mL) at a temperature of22-27° C. The resulting mixture was stirred at 22° C. for 1 h and pouredonto ice. The aqueous phase was extracted with ethyl acetate, and thecombined organic phases were washed with brine, dried (MgSO₄) andconcentrated in vacuo. The crude product was purified by flashchromatography on silicagel (eluent:ethyl acetate/heptane/triethylamine50:50:5) to give the product as an orange oil (2.4 g). The titlecompound was isolated as the oxalate salt from acetone as a whitecrystalline compound (0.6 g). Mp 188-189° C. ¹H NMR (DMSO-d₆): 1.85-2.05(m, 4H); 2.10 (d, 2H); 2.55 (t, 2H); 2.90 (t, 2H); 2.95-3.05 (m, 3H);3.10 (t, 2H); 3.50 (d, 2H); 3.75 (s, 3H); 3.95 (t, 2H); 6.95-7.05 (m,2H); 7.15-7.30 (m, 4H); 7.35-7.45 (m, 2H). MS m/z: 420 (MH+), 188.

[0193] The following compounds were prepared in a similar manner

[0194] 5b,5-Fluoro-1-methyl-3-{1-[4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)butan-1-yl]piperidin-4-yl}-1H-indole,hydrochloride

[0195] from5-fluoro-3-{1-[4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)butan-1-yl]piperidin-4-yl}-1H-indoleand methyl iodide. Mp 177-179° C. ¹H NMR (DMSO-d₆): 1.55-1.65 (m, 2H);1.75-1.85 (m, 2H); 2.00-2.15 (m, 4H); 2.55 (t, 2H); 2.90 (t, 2H);2.95-3.15 (m, 5H); 3.55 (d, 2H); 3.75 (s, 3H); 3.95 (t, 2H); 6.95-7.05(m, 2H); 7.15 (d, 1H); 7.20-7.30 (m, 3H); 7.35-7.45 (m, 1H); 7.55 (d,1H); 11.40 (broad s, 1H). MS m/z: 434 (MH+).

[0196] 5c,1-(Butan-1-yl)-5-fluoro-3-{1-[4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)butan-1-yl]-3,6-dihydro-2H-pyridin-4-yl}-1H-indole,oxalate

[0197] from5-fluoro-3-{1-[4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)butan-1-yl]-3,6-dihydro-2H-pyridin-4-yl}-1H-indoleand butyl bromide. Mp 152-154° C. ¹H NMR (DMSO-d₆): 0.90 (t, 3H);1.20-1.30 (m, 2H); 1.55-1.65 (m, 2H); 1.65-1.80 (m, 4H); 2.55 (t, 2H);2.75 (s, 2H); 2.85 (t, 2H); 3.10 (t, 2H); 3.35 (s, 2H); 3.80 (s, 2H);3.95 (t, 2H); 4.15 (t, 2H); 6.10 (s, 1H); 6.95-7.05 (m, 2H); 7.15 (d,1H); 7.20-7.30 (m, 2H); 7.50-7.55 (m, 1); 7.55-7.70 (m, 2H). MS m/z: 474(MH+), 231.

Example 6

[0198] 6a,5-Fluoro-3-{1-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-3-oxopropan-1-yl]piperidin-4-yl}-1H-indole,oxalate

[0199] A mixture of 5-fluoro-3-(piperidin-4-yl)-1H-indole (3.0 g),butanone (200 mL), tetrahydrofuran (100 mL), methanol (50 mL) andtriethylamine (2.4 mL) was heated until reflux temperature followed bythe addition of a solution of3-chloro-1-(3,4-dihydro-1H-isoquinolin-2-yl)propan-1-one (3.5 g) inbutanone (60 mL). The mixture was boiled under reflux for 30 h followedby the addition of an additional amount of3-chloro-1-(3,4-dihydro-1H-isoquinolin-2-yl)propan-1-one (2.0 g) andtriethylamine (1.6 mL) in tetrahydrofuran (50 mL). The resulting mixturewas boiled under reflux for an additional 12 h. The mixture was cooled,filtered and concentrated in vacuo. The residue was purified by flashchromatography on silicagel (eluent:ethyl acetate/ethanol/triethylamine100:4:4) to give the crude product. The title compound was isolated asthe oxalate salt from acetone as a white crystalline compound (0.75 g).Mp 206-209° C. ¹H NMR (DMSO-d₆): 1.95 (q, 2H); 2.05-2.15 (m, 2H); 2.80(t, 0.8H); 2.90 (t, 1.2H); 2.90-3.10 (m, 5H); 3.30 (t, 2H); 3.55 (d,2H); 3.70 (t, 2H); 4.65 (s, 1.20H); 4.70 (s, 0.8H); 6.85-6.95 (m, 1H);7.15-7.25 (m, 5H); 7.30-7.40 (m, 1H); 7.40 (d, 1H); 11.05 (s, 1H). MSm/z: 406 (MH+), 231.

[0200] The following compound was prepared in a similar manner

[0201] 6b,7-Chloro-3-{1-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-3-oxopropan-1-yl]piperidin-4-yl}-1H-indole,hydrochloride

[0202] from 7-chloro-3-(piperidin-4-yl)-1H-indole and3-bromo-1-(3,4-dihydro-1H-isoquinolin-2-yl)propan-1-one. ¹H NMR(DMSO-d₆): 2.05-2.25 (m, 4H); 2.80 (t, 0.8H); 2.95 (t, 1.2H); 3.00-3.20(m, 5H); 3.30-3.45 (m, 2H); 3.55-3.65 (m, 2H); 3.65-3.75 (m, 2H); 4.65(s, 1.2H); 4.75 (s, 0.8H); 7.00 (t, 1H); 7.15-7.25 (m, 6H); 7.70 (d,1H); 10.70 (broad s, 1H); 11.30 (s, 1H). MS m/z: 422 (MH+), 247.

[0203] 6c.5-Chloro-3-{1-[4-(3,4-dihydro-2H-quinolin-1-yl)-4-oxobutan-1-yl]piperidin-4-yl}-1H-indole,hydrochloride from 5-chloro-3-(piperidin-4-yl)-1H-indole and4-chloro-1-(3,4-dihydro-2H-quinolin-1-yl)butan-1-one. Mp 158-162° C. ¹HNMR (DMSO-d₆): 1.85-1.95 (m, 2H); 1.95-2.20 (m, 6H); 2.60-2.75 (m, 4H);2.95-3.15 (m, 5H); 3.55 (d, 2H); 3.70 (t, 2H); 7.05-7.25 (m, 6H); 7.40(d, 1H); 7.75 (s, 1H); 10.45 (broad s, 1H); 11.15 (s, 1H). MS m/z: 436(MH+), 303.

Example 7

[0204] 7,5-Fluoro-3-{1-[4-(3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutan-1-yl]piperidin-4-yl}-1H-indole

[0205] A mixture of 5-fluoro-3-(piperidin-4-yl)-1H-indole (3.0 g),butanone (200 mL), tetrahydrofuran (200 mL), methanol (30 mL), potassiumiodide (11.4 g) and triethylamine (7.6 mL) was heated until refluxtemperature followed by the addition of a solution of4-chloro-1-(3,4-dihydro-1H-isoquinolin-2-yl)butan-1-one (14.6 g) inbutanone (50 mL). The mixture was boiled under reflux for 2 h, filteredhot and concentrated in vacuo. The residue was purified by flashchromatography on silicagel (eluent:ethyl acetate/ethanol/triethylamine100:5:5) to give the crude product. The title compound was isolated asthe free base from ethyl acetate as a white crystalline compound (0.9g). Mp 146-148° C. ¹H NMR (DMSO-d₆): 1.55-1.70 (m, 2H); 1.70-1.80 (m,2H); 1.85-1.95 (m, 2H); 2.00 (q, 2H); 2.30 (q, 2H); 2.35-2.45 (m, 2H);2.60-2.70 (m, 1H); 2.75 (t, 0.8H); 2.80-3.00 (m, 3.2H); 3.65 (t, 2H);4.60 (s, 1.2H); 4.70 (s, 0.8H); 6.85-6.95 (m, 1H); 7.10-7.20 (m, 5H);7.25 (d, 1H); 7.30-7.35 (m, 1H); 10.85 (s, 1H). MS m/z: 420 (MH+), 202.

Example 8

[0206] 8,5-Chloro-3-{1-[4-(3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutan-1-yl]piperidin-4-yl}-1H-indole

[0207] A mixture of 5-fluoro-3-(piperidin-4-yl)-1H-indole (3.0 g),butanone (200 mL) and triethylamine (8.9 mL) was heated until refluxtemperature followed by the addition of a solution of4-chloro-1-(3,4-dihydro-1H-isoquinolin-2-yl)butan-1-one (15.2 g) inbutanone (80 mL). The mixture was boiled under reflux for 6 h. Theresulting mixture was filtered and concentrated in vacuo. The residuewas purified by flash chromatography on silicagel (eluent:ethylacetate/ethanol/triethylamine 100:4:4) to give the crude product. Thetitle compound was isolated as the free base from acetone as a whitecrystalline compound (0.6 g). Mp 172-175° C. ¹H NMR (DMSO-d₆): 1.55-1.65(m, 2H); 1.65-1.75 (m, 2H); 1.90 (s, 2H); 2.00 (q, 2H); 2.30 (q, 2H);2.40 (q, 2H); 2.65-2.80 (m, 1.8H); 2.80-3.00 (m, 3.2H); 3.70 (t, 2H);4.60 (s, 1.2H); 4.70 (s, 0.8H); 7.05 (d, 1H); 7.10-7.25 (m, 5H); 7.35(d, 1H); 7.55 (s, 1H); 11.00 (s, 1H). MS m/z: 436 (MH+), 202.

Example 9

[0208] 9a,5-Fluoro-3-{1-[3-(3,4-dihydro-2H-quinolin-1-yl)propan-1-yl]piperidin-4-yl}-1H-indole,dihydrochloride

[0209] A suspension of lithium aluminium hydride (0.94 g) intetrahydrofuran (40 mL) was stirred at 5° C. followed by the addition ofconcentrated sulphuric acid (1.2 g) in tetrahydrofuran (20 mL). Themixture was stirred at 7° C. for 60 min followed by the addition of5-fluoro-3-{1-[3-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)propan-1-yl]piperidin-4-yl}-1H-indole(2.0 g) in tetrahydrofuran (60 mL). The resulting mixture was stirred at5° C. for 60 min followed by standard work up. The residue was purifiedby flash chromatography on silicagel (eluent: ethyl acetate) to give thecrude product as a colourless oil. The title compound was isolated asthe dihydrochloride salt from tetrahydrofuran as a white crystallinecompound (1.0 g). Mp 230-236° C. ¹H NMR (DMSO-d₆): 1.95 (t, 2H);2.00-2.30 (m, 4H); 2.75 (t, 2H); 2.95-3.20 (m, 5H); 3.30 (t, 2H); 3.40(t, 2H); 3.55 (d, 2H) 6.20 (broad s, 1H); 6.70 (broad s, 1H); 6.95 (m,2H); 7.00 (d, 1H); 7.10 (t, 1H); 7.20 (s, 1H); 7.30-7.40 (m, 1H); 7.50(d, 1H); 10.95 (broad s, 1H); 11.05 (s, 1H). MS m/z: 392 (MH+), 259.

[0210] The following compounds were prepared in a similar manner

[0211] 9b,5-Fluoro-3-{1-[4-(3,4-dihydro-2H-quinolin-1-yl)butan-1-yl]piperidin-4-yl}-1H-indole,dihydrochloride

[0212] from5-fluoro-3-{1-[4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)butan-1-yl]piperidin-4-yl}-1H-indole.Mp 207-212° C. ¹H NMR (DMSO-d₆): 1.65 (s, 2H); 1.80-1.90 (m, 2H); 1.95(s, 2H); 2.05 (d, 2H); 2.20 (q, 2H); 2.65-2.80 (m, 2H); 2.95-3.25 (m,4H); 3.15-3.25 (m, 1H); 3.35 (s, 4H); 3.55 (d, 2H); 4.65 (broad s);5.55-6.95 (m, 3H); 7.00 (s, 1H); 7.10 (s, 1H); 7.20 (s, 1H); 7.30-7.40(m, 1H); 7.55 (d, 1H); 11.75 (broad s, 1H); 11.05 (s, 1H). MS m/z: 406(MH+), 274.

[0213] 9c,5-Fluoro-3-{1-[5-(3,4-dihydro-2H-quinolin-1-yl)pentan-1-yl]piperidin-4-yl}-1H-indole,dihydrochloride

[0214] from5-fluoro-3-{1-[5-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)pentan-1-yl]piperidin-4-yl}-1H-indole.Mp 155-158° C. ¹H NMR (DMSO-d₆): 1.30-145 (m, 2H); 1.65 (s, 2H);1.75-1.80 (m, 2H); 1.95 (s, 2H); 2.20 (q, 2H); 2.75 (s, 2H); 2.95-3.10(m, 5H); 3.35 (s, 4H); 3.55 (d, 2H); 5.05 (broad s); 6.70-7.15 (m, 4H);6.90 (t, 1H); 7.20 (s, 1H); 7.30-7.40 (m, 1H); 7.50 (d, 1H); 10.75(broad s, 1H); 11.05 (s, 1H). MS m/z: 420 (MH+), 287.

[0215] 9d,5-Chloro-3-{1-[3-(3,4-dihydro-2H-quinolin-1-yl)propan-1-yl]piperidin-4-yl}-1H-indole,dihydrochloride

[0216] from5-chloro-3-{1-[3-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)propan-1-yl]piperidin-4-yl}-1H-indole.Mp 201-204° C. ¹H NMR (DMSO-d₆): 1.95 (t, 2H); 2.00-2.25 (m, 6H); 2.75(t, 2H); 3.00-3.20 (m, 5H); 3.30 (t, 2H); 3.40 (t, 2H); 3.55 (d, 2H);6.40 (broad s); 6.65 (s, 1H); 6.85 (s, 1H); 6.95 (d, 1H); 7.00-7.10 (m,2H); 7.20 (s, 1H); 7.40 (d, 1H); 7.75 (s, 1H); 10.85 (broad s, 1H);11.20 (s, 1H). MS m/z: 408 (MH+), 275.

[0217] 9e.5-Chloro-3-{1-[4-(3,4-dihydro-2H-quinolin-1-yl)butan-1-yl]piperidin-4-yl}-1H-indole,dihydrochloride

[0218] from5-chloro-3-{1-[4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)butan-1-yl]piperidin-4-yl}-1H-indole.Mp 140-145° C. ¹H NMR (DMSO-d₆): 1.65 (s, 2H); 1.80-1.90 (m, 2H); 1.95(s, 2H); 2.00-2.25 (m, 4H); 2.75 (s, 2H); 2.95-3.25 (m, 5H); 3.35 (s,4H); 3.55 (d, 2H); 6.75 (broad s, 1H); 6.90 (broad s, 1H); 7.00 (s, 1H);7.05-7.15 (m, 2H); 7.20 (s, 1H); 7.40 (d, 1H); 7.80 (s, 1H); 10.70(broad s, 1H); 11.20 (s, 1H). MS m/z: 422 (MH+), 289, 188.

[0219] 9f,5-Chloro-3-{1-[5-(3,4-dihydro-2H-quinolin-1-yl)pentan-1-yl]piperidin-4-yl}-1H-indole,dihydrochloride

[0220] from5-chloro-3-{1-[5-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)pentan-1-yl]piperidin-4-yl}-1H-indole.Mp 101-106° C. ¹H NMR (DMSO-d₆): 1.30-1.45 (m, 2H); 1.65 (s, 2H);1.70-1.85 (m, 2H); 1.95 (s, 2H); 2.00-2.25 (m, 4H); 2.75 (s, 2H);2.95-3.25 (m, 5H); 3.35 (s, 4H); 3.55 (d, 2H); 6.80 (broad s, 1H);6.90-7.15 (m, 4H); 7.20 (s, 1H); 7.35 (d, 1H); 7.75 (s, 1H); 10.70(broad s, 1H); 11.20 (s, 1H). MS m/z: 436 (MH+), 303.

[0221] 9g,7-Chloro-3-{1-[4-(3,4-dihydro-2H-quinolin-1-yl)butan-1-yl]piperidin-4-yl}-1H-indole,dihydrochloride

[0222] from7-chloro-3-{1-[4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)butan-1-yl]piperidin-4-yl}-1H-indole.Mp 214-219° C. ¹H NMR (DMSO-d₆): 1.65 (s, 2H); 1.80-1.90 (m, 2H); 1.95(s, 2H); 2.00-2.15 (m, 2H); 2.15-2.30 (m, 2H); 2.70 (s, 2H); 2.95-3.15(m, 5H); 3.35 (s, 4H); 3.55 (d, 2H); 6.70 (broad s, 1H); 6.85 (broad s,1H); 6.95-7.05 (m, 2H); 7.10 (s, 1H); 7.15-7.25 (m, 2H); 7.70 (d, 1H);10.80 (broad s, 1H); 11.30 (s, 1H). MS m/z: 422 (MH+), 289, 188.

[0223] 9h,5-Fluoro-1-methyl-3-{1-[3-(3,4-dihydro-2H-quinolin-1-yl)propan-1-yl]piperidin-4-yl}-1H-indole,dihydrochloride

[0224] from5-fluoro-1-methyl-3-{1-[3-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)propan-1-yl]piperidin-4-yl}-1H-indole.Mp 202-206° C. ¹H NMR (DMSO-d₆): 1.85-1.95 (m, 2H); 2.00-2.10 (m, 4H);2.10-2.25 (m, 2H); 2.65-2.75 (m, 2H); 2.95-3.15 (m, 5H); 3.25-3.35 (m,2H); 3.35-3.40 (m, 2H); 3.55 (d, 2H); 3.75 (s, 3H); 6.65 (broad s, 1H);6.80 (broad s, 1H); 6.90-7.10 (m, 3H); 7.20 (s, 1H); 7.35-7.45 (m, 1H);7.55 (d, 1H); 10.90 (broad s, 1H). MS m/z: 406 (MH+), 273.

[0225] 9i,5-Fluoro-1-methyl-3-{1-[4-(3,4-dihydro-2H-quinolin-1-yl)butan-1-yl]piperidin-4-yl}-1H-indole,oxalate

[0226] from5-fluoro-1-methyl-3-{1-[4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)butan-1-yl]piperidin-4-yl}-1H-indole.Mp 123-125° C. ¹H NMR (DMSO-d₆): 1.50-1.60 (m, 2H); 1.65-1.75 (m, 2H);1.80-1.90 (m, 2H); 1.90-2.00 (m, 2H); 2.10 (d, 2H); 2.60-2.70 (m, 2H);2.95-3.10 (m, 5H); 3.20-3.30 (m, 4H); 3.50 (d, 2H); 3.75 (s, 3H); 6.45(t, 1H); 6.60 (d, 1H); 6.85 (d, 1H); 6.95-7.05 (m, 2H); 7.20 (s, 1H);7.40-7.45 (m, 2H). MS m/z: 420 (MH+), 287.

[0227] 9j,5-Fluoro-3-{1-[4-(3,4-dihydro-2H-1,4-benzoxazin-4-yl)butan-1-yl]piperidin-4-yl}-1H-indole,dihydrochloride

[0228] from5-fluoro-3-{1-[4-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl)butan-1-yl]piperidin-4-yl}-1H-indole.Mp 179-186° C. ¹H NMR (DMSO-d₆): 1.55-1.65 (m, 2H); 1.75-1.90 (m, 2H);2.00-2.10 (m, 2H); 2.15-2.25 (m, 2H); 2.95-3.25 (m, 5H); 3.25-3.40 (m,4H); 3.55 (d, 2H); 4.15-4.25 (m, 2H); 6.55 (t, 1H); 6.65 (d, 1H);6.70-6.80 (m, 2H); 6.90 (t, 1H); 7.20 (s, 1H); 7.30-7.40 (m, 1H); 7.55(d, 1H); 10.80 (broad s, 1H); 11.05 (s, 1H). MS m/z: 408 (MH+), 273,190.

[0229] 9k,5-Chloro-3-{1-[4-(3,4-dihydro-2H-1,4-benzoxazin-4-yl)butan-1-yl]piperidin-4-yl}-1H-indole,dihydrochloride

[0230] from5-chloro-3-{1-[4-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl)butan-1-yl]piperidin-4-yl}-1H-indole.Mp 186-190° C. ¹H NMR (DMSO-d₆): 1.55-1.65 (m, 2H); 1.70-1.85 (m, 2H);2.00-2.20 (m, 4H); 2.95-3.25 (m, 5H); 3.25-3.40 (m, 4H); 3.55 (d, 2H);4.15-4.20 (m, 2H); 6.55 (t, 1H); 6.65 (d, 1H); 6.70-6.80 (m, 2H); 7.05(d, 1H); 7.20 (s, 1H); 7.40 (d, 1H); 7.75 (s, 1H); 10.50 (broad s, 1H);11.15 (s, 1H). MS m/z: 424 (MH+), 289, 190.

[0231] 9l,5-Fluoro-3-{1-[3-(3,4-dihydro-2H-quinolin-1-yl)propan-1-yl]-3,6-dihydro-2H-pyridin-4-yl}-1H-indole,dihydrochloride

[0232] from5-fluoro-3-{1-[3-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)propan-1-yl]-3,6-dihydro-2H-pyridin-4-yl}-1H-indole.Mp 220-223° C. ¹H NMR (DMSO-d₆): 1.85-2.00 (m, 2H); 2.05-2.10 (m, 2H);2.70-2.80 (m, 4H); 2.90-3.00 (m, 1H); 3.15-3.30 (m, 2H); 3.30-3.35 (m,2H); 3.40 (t, 2H); 3.55-3.65 (m, 1H); 3.70-3.80 (m, 1H); 4.00 (d, 1H);6.10 (s, 1H); 6.70 (broad s, 1H); 6.90 (broad s, 1H); 6.95-7.05 (m, 2H);7.05-7.10 (m, 1H); 7.40-7.45 (m, 1H); 7.55-7.65 (m, 2H); 11.10 (broad s,1H); 11.60 (s, 1H). MS m/z: 390 (MH+), 203, 146.

[0233] 9m,5-Fluoro-3-{1-[4-(3,4-dihydro-2H-quinolin-1-yl)butan-1-yl]-3,6-dihydro-2H-pyridin-4-yl}-1H-indole,dihydrochloride

[0234] from5-fluoro-3-{1-[4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)butan-1-yl]-3,6-dihydro-2H-pyridin-4-yl}-1H-indole.Mp 198-200° C. ¹H NMR (DMSO-d₆): 1.60-1.75 (m, 2H); 1.80-1.90 (m, 2H);1.95 (s, 2H); 2.70-2.80 (m, 4H); 2.85-3.00 (m, 1H); 3.15-3.30 (m, 4H);3.30-3.40 (m, 2H); 3.55-3.65 (m, 1H); 3.70-3.80 (m, 1H); 3.95 (d, 1H);6.10 (s, 1H); 6.80 (broad s, 1H); 6.90-7.20 (m, 3H); 7.00 (t, 1H);7.40-7.45 (m, 1H); 7.55-7.65 (m, 2H); 10.95 (broad s, 1H); 11.55 (s,1H). MS m/z: 404 (MH+), 271, 217.

[0235] 9n,5-Fluoro-3-{1-[5-(3,4-dihydro-2H-quinolin-1-yl)pentan-1-yl]-3,6-dihydro-2H-pyridin-4-yl}-1H-indole,dihydrochloride

[0236] from5-fluoro-3-{1-[5-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)pentan-1-yl]-3,6-dihydro-2H-pyridin-4-yl}-1H-indole.Mp 167-169° C. ¹H NMR (DMSO-d₆): 1.30-1.45 (m, 2H); 1.70 (s, 2H);1.75-1.90 (m, 2H); 2.00 (s, 2H); 2.70-2.85 (m, 3H); 2.85-3.00 (m, 1H);3.05-3.20 (m, 2H); 3.20-3.30 (m, 1H); 3.35 (s, 2H); 3.55-3.65 (m, 1H);3.70-3.80 (m, 1H); 3.95 (d, 1H); 6.10 (s, 1H); 6.80-7.25 (m, 4H); 7.00(t, 1H); 7.40-7.45 (m, 1H); 7.55-7.65 (m, 2H); 11.00 (s, broad s, 1H);11.60 (s, 1H). MS m/z: 418 (MH+), 231, 188.

Example 10

[0237] 10a,4-Fluoro-3-{1-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-3-oxopropan-1-yl]piperidin-4-yl}-1H-indole

[0238] Polymer bound3-[1-(4-fluoro-1H-indol-3-yl)piperidin-1-yl)propionic acid (0.1 g, 0.08mmol) and dry dichloromethane (1 mL) were mixed in a reactor tube. Themixture was cooled to 0° C. and treated for 2 h with a 2 M solution ofthionyl chloride (0.4 mL, 0.8 mmol) in dichloromethane. The resin wasfiltered off and washed with dry dichloromethane (3×1 mL), resuspendedin dichloromethane (1 mL), and treated for 3 h at room temperature with3,4-dihydro-1H-isoquinoline (0.05 g, 0.4 mmol). The resin was filteredoff and washed with dichloromethane (3×1 mL), a 1:1 mixture ofdichloromethane:triethylamine (3×1 mL) and dry dichloromethane (3×1 mL).The resin was treated for 1 h with 1 mL of a mixture of sodium methoxide(2 mL, 5 N sodium methoxide in methanol), methanol (50 mL) andtetrahydrofuran (50 mL). After filtration, the resin was washed withmethanol (1 mL). The combined filtrates were loaded on a pre-conditionedion exchange column (500 mg SCX column, commercially available fromAnalytical Instruments, part no. 1210-2040), washed with acetonitrile (1mL) and methanol (1 mL). The product was eluted with 4 M ammonia inmethanol. After evaporation of volatile solvents, the crude product waspurified by preparative reversed phase HPLC chromatography. Theresulting solution was subsequently loaded on a pre-conditioned ionexchange column washed with acetonitrile (1 mL) and methanol (1 mL). Theproduct was eluted with 4 M ammonia in methanol. Evaporation of volatilesolvents afforded the title compound as an yellow oil (5 mg, 12 μmol).LC/MS (m/z) 406 (MH+), RT=3.61, purity: 66%.

[0239] The following compounds were prepared in a similar manner(10b-10m) or by the use of 3,4-dihydro-2H-quinoline (10n-10z):

[0240] 10b,4-Fluoro-3-{1-[4-(3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutan-1-yl]piperidin-4-yl}-1H-indole

[0241] LC/MS (m/z) 420 (MH+), RT=3.69, purity: 93%

[0242] 10c,4-Fluoro-3-{1-[6-(3,4-dihydro-1H-isoquinolin-2-yl)-6-oxohexan-1-yl]piperidin-4-yl}-1H-indole

[0243] LC/MS (m/z) 448 (MH+), RT=3.81, purity: 97%

[0244] 10d,4-Chloro-3-{1-[4-(3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutan-1-yl]piperidin-4-yl}-1H-indole

[0245] LC/MS (m/z) 436 (MH+), RT=3.86, purity: 97%

[0246] 10e,4-Chloro-3-{1-[5-(3,4-dihydro-1H-isoquinolin-2-yl)-5-oxopentan-1-yl]piperidin-4-yl}-1H-indole

[0247] LC/MS (m/z) 450 (MH+), RT=3.87, purity: 81%

[0248] 10f,4-Chloro-3-{1-[6-(3,4-dihydro-1H-isoquinolin-2-yl)-6-oxohexan-1-yl]piperidin-4-yl}-1H-indole

[0249] LC/MS (m/z) 464 (MH+), RT=3.97, purity: 86%

[0250] 10g,5-Fluoro-3-{1-[5-(3,4-dihydro-1H-isoquinolin-2-yl)-5-oxopentan-1-yl]piperidin-4-yl}-1H-indole

[0251] LC/MS (m/z) 434 (MH+), RT=3.67, purity: 93%

[0252] 10h,5-Fluoro-3-{1-[6-(3,4-dihydro-1H-isoquinolin-2-yl)-6-oxohexan-1-yl]piperidin-4-yl}-1H-indole

[0253] LC/MS (m/z) 448 (MH+), RT=3.79, purity: 89%

[0254] 10i,6-Chloro-3-{1-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-3-oxopropan-1-yl]piperidin-4-yl}-1H-indole

[0255] LC/MS (m/z) 422 (MH+), RT=3.80, purity: 85%

[0256] 10j,6-Chloro-3-{1-[6-(3,4-dihydro-1H-isoquinolin-2-yl)-6-oxohexan-1-yl]piperidin-4-yl}-1H-indole

[0257] LC/MS (m/z) 464 (MH+), RT=3.98, purity: 87%

[0258] 10k,7-Chloro-3-{1-[4-(3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutan-1-yl]piperidin-4-yl}-1H-indole

[0259] LC/MS (m/z) 436 (MH+), RT=3.85, purity: 98%

[0260] 10l,7-Chloro-3-{1-[5-(3,4-dihydro-1H-isoquinolin-2-yl)-5-oxopentan-1-yl]piperidin-4-yl}-1H-indole

[0261] LC/MS (m/z) 450 (MH+), RT=3.85, purity: 96%

[0262] 10m,7-Chloro-3-{1-[6-(3,4-dihydro-1H-isoquinolin-2-yl)-6-oxohexan-1-yl]piperidin-4-yl}-1H-indole

[0263] LC/MS (m/z) 464 (MH+), RT=3.96, purity: 97%

[0264] 10n,4-Fluoro-3-{1-[3-(3,4-dihydro-2H-quinolin-1-yl)-3-oxopropan-1-yl]piperidin-4-yl}-1H-indole

[0265] LC/MS (m/z) 406 (MH+), RT=3.67, purity: 82%

[0266] 10o,4-Fluoro-3-{1-[4-(3,4-dihydro-2H-quinolin-1-yl)-4-oxobutan-1-yl]piperidin-4-yl}-1H-indole

[0267] LC/MS (m/z) 420 (MH+), RT=3.78, purity: 84%

[0268] 10p,4-Chloro-3-{1-[3-(3,4-dihydro-2H-quinolin-1-yl)-3-oxopropan-1-yl]piperidin-4-yl}-1H-indole

[0269] LC/MS (m/z) 422 (MH+), RT=3.85, purity: 97%

[0270] 10q,4-Chloro-3-{1-[4-(3,4-dihydro-2H-quinolin-1-yl)-4-oxobutan-1-yl]piperidin-4-yl}-1H-indole

[0271] LC/MS (m/z) 436 (MH+), RT=3.97, purity: 92%

[0272] 10r,5-Fluoro-3-{1-[3-(3,4-dihydro-2H-quinolin-1-yl)-3-oxopropan-1-yl]piperidin-4-yl}-1H-indole

[0273] LC/MS (m/z) 406 (MH+), RT=3.63, purity: 97%

[0274] 10s,5-Fluoro-3-{1-[4-(3,4-dihydro-2H-quinolin-1-yl)-4-oxobutan-1-yl]piperidin-4-yl}-1H-indole

[0275] LC/MS (m/z) 420 (MH+), RT=3.73, purity: 96%

[0276] 10t,5-Fluoro-3-{1-[5-(3,4-dihydro-2H-quinolin-1-yl)-5-oxopentan-1-yl]piperidin-4-yl}-1H-indole

[0277] LC/MS (m/z) 434 (MH+), RT=3.76, purity: 97%

[0278] 10u,5-Fluoro-3-{1-[6-(3,4-dihydro-2H-quinolin-1-yl)-6-oxohexan-1-yl]piperidin-4-yl}-1H-indole

[0279] LC/MS (m/z) 448 (MH+), RT=3.88, purity: 97%

[0280] 10v,6-Chloro-3-{1-[3-(3,4-dihydro-2H-quinolin-1-yl)-3-oxopropan-1-yl]piperidin-4-yl}-1H-indole

[0281] LC/MS (m/z) 422 (MH+), RT=3.88, purity: 90%

[0282] 10w,6-Chloro-3-{1-[6-(3,4-dihydro-2H-quinolin-1-yl)-6-oxohexan-1-yl]piperidin-4-yl}-1H-indole

[0283] LC/MS (m/z) 464 (MH+), RT=4.09, purity: 96%

[0284] 10x,7-Chloro-3-{1-[4-(3,4-dihydro-2H-quinolin-1-yl)-4-oxobutan-1-yl]piperidin-4-yl}-1H-indole

[0285] LC/MS (m/z) 436 (MH+), RT=3.91, purity: 98%

[0286] 10y,7-Chloro-3-{1-[5-(3,4-dihydro-2H-quinolin-1-yl)-5-oxopentan-1-yl]piperidin-4-yl}-1H-indole

[0287] LC/MS (m/z) 450 (MH+), RT=3.93, purity: 96%

[0288] 10z,7-Chloro-3-{1-[6-(3,4-dihydro-2H-quinolin-1-yl)-6-oxohexan-1-yl]piperidin-4-yl}-1H-indole

[0289] LC/MS (m/z) 464 (MH+), RT=4.05, purity: 97%

Example 11

[0290] 11a,5-Fluoro-3-{1-[4-(3,4-dihydro-1H-isoquinolin-2-yl)butan-1-yl]piperidin-4-yl}-1H-indole,dioxalate

[0291] A mixture of 5-fluoro-3-(piperidin-4-yl)-1H-indole (5.0 g),triethylamine (6.35 mL) and tetrahydrofuran (500 mL) was cooled to 7° C.and subsequently added a mixture of succinic anhydride (2.5 g) intetrahydrofuran (50 mL). The mixture was stirred at 8-10° C. for 2 h,and the solvent was removed in vacuo. The residue was dissolved in ethylacetate, and the organic phase was washed with cold 2N aqueoushydrochloride solution and brine. The organic phase was dried (MgSO₄),filtered and concentrated in vacuo (6.4 g). The residue (1.5 g) and3,4-dihydro-1H-isoquinoline (0.63 g) was dissolved in a mixture ofacetonitril (25 mL) and dimethyl formamide (10 mL), and the resultingmixture was cooled (5° C.) and subsequently added1,3-dicyclohexylcarbodiimide (1.0 g). The mixture was stirred at roomtemperature for 16 h, filtered and poured into brine. The aqueous phasewas extracted with ethyl acetate and tetrahydrofuran, and the combinedorganic phase was washed with brine, dried (MgSO₄) and concentrated invacuo. The residue was purified by flash chromatography on silicagel(eluent:ethyl acetate) to give a white solid (1.0 g), which subsequentlywas added to a mixture of alane in tetrahydrofuran (100 mL) at 5-10° C.The alane was prepared from lithium aluminium hydride (0.55 g) andconcentrated sulphuric acid (0.72 g). The mixture was quenched by theaddition of water (1 mL), 15% aqueous sodium hydroxide solution (0.5 mL)and water (2.5 mL), and the resulting mixture was dried (MgSO₄),filtered and concentrated in vacuo. The title compounds was crystallisedfrom acetone as the dioxalate salt (0.8 g). Mp 105-111° C. ¹H NMR(DMSO-d₆): 1.75 (s, 4H); 1.85-2.05 (m, 2H); 2.10 (d, 2H); 2.90-3.20 (m,9H); 3.25 (t, 2H); 3.50 (d, 2H); 4.15 (s, 2H); 6.85-6.95 (m, 1H);7.10-7.25 (m, 5H); 7.30-7.45 (m, 2H); 11.05 (s, 1H). MS m/z: 406 (MH+),273, 188.

[0292] The following compound was prepared in a similar manner

[0293] 11b,5-Fluoro-3-{1-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)butan-1-yl]piperidin-4-yl}-1H-indole,dioxalate

[0294] from 5-fluoro-3-(piperidin-4-yl)-1H-indole and6,7-dimethoxy-3,4-dihydro-1H-isoquinoline. Mp 98-105° C. ¹H NMR(DMSO-d₆): 1.75 (s, 4H); 1.85-2.00 (m, 2H); 2.10 (d, 2H); 2.90-3.15 (m,9H); 3.30 (s, 2H); 3.50 (d, 2H); 3.75 (d, 6H); 4.10 (s, 2H); 6.75 (s,1H); 6.80 (s, 1H); 6.90-6.95 (m, 1H); 7.20 (s, 1H); 7.30-7.45 (m, 2H);11.05 (s, 1H). MS m/z: 466 (MH+), 273, 248.

[0295] Pharmacological Testing

[0296] The compounds of the invention were tested in well-recognised andreliable tests. The tests were as follows:

[0297] Inhibition of the Binding of [³H]YM-09151-2 to Human Dopamine D₄Receptors

[0298] By this method, the inhibition by drugs of the binding of[³H]YM-09151-2 (0.06 nM) to membranes of human cloned dopamine D_(4.2)receptors expressed in CHO-cells is determined in vitro. Method modifiedfrom NEN Life Science Products, Inc., technical data certificatePC2533-10/96.

[0299] In table 1 below, the test results are shown: TABLE 1 Comp. No.D₄-bind. 1a 92%  1b 97%  1c 95%  2a 0.58  2b 12  2c 0.69  2d 8.0  2e 12 2f 78%  2g 7.5  2h 10  3a 0.71  3b 5.0  3c 15  4 4.8  9l 0.51  9m 17 9n 53 10a 93% 10b 81% 10c 21% 10d 86% 10e 25% 10f 17% 10g 65% 10h 50%10i 94% 10j 70% 10k 95% 10l 82% 10m 69%

[0300] The compounds of the invention have been found potently toinhibit the binding of tritiated YM-09151-2 to dopamine D₄ receptors.

[0301] The compounds have also been tested in a functional assaydescribed by Gazi et al. in British Journal of Pharmacology 1999, 128,613-620. In this test, the compounds were shown to be partial agonistsor antagonists at the dopamine D₄ receptors.

[0302] The compounds of the invention have also been tested in thefollowing tests:

[0303] Inhibition of the Binding of [³ H]Spiperone to D₂ Receptors

[0304] The compounds of the invention were tested with respect toaffinity for the dopamine D₂ receptor by determining their ability toinhibit the binding of [³H]spiperone to D₂ receptors by the method ofHyttel et al. J. Neurochem. 1985, 44, 1615.

[0305] Inhibition of the Binding of [³H]Spiperone to Human D₃ Receptors

[0306] By this method, the inhibition by drugs of the binding[³H]Spiperone (0.3 nM) to membranes of human cloned dopamine D₃receptors expressed in CHO-cells is determined in vitro. Method modifiedfrom MacKenzie et al. Eur. J Pharm.-Mol. Pharm. Sec. 1994, 266, 79-85.

[0307] Inhibition of the Uptake of [³H]Serotonin into Whole Rat BrainSynaptosomes

[0308] The compounds were tested with respect to their 5-HT reuptakeinhibiting effect by measuring their ability to inhibit the uptake of[³H]serotonin into whole rat brain synaptosomes in vitro. The assay wasperformed as described by Hyttel Psychopharmacology 1978, 60, 13.

[0309] Inhibition of the Binding of [³H]Ketanserin to 5-HT_(2A)Receptors

[0310] The compounds were tested with respect to their affinity for5-HT_(2A) receptors by determining their ability to inhibit the bindingof [³H]Ketanserin (0.50 nM) to membranes from rat brain (cortex) invitro. Method described in Sánchez et al. Drug Dev. Res. 1991, 22,239-250.

[0311] 5-HT_(2C) Receptor Efficacy as Determined by Fluorometry

[0312] The compounds were tested with respect to their efficacy on5-HT_(2C) receptor-expressing CHO cells as determined by fluorometricimaging plate reader (FLIPR) analysis. This assay was carried outaccording to Molecular Devices Inc. instructions for their FLIPR CalciumAssay Kit and as modified from Porter et al. British Journal ofPharmacology 1999, 128:13.

[0313] The compounds were found to have no substantial or only weakaffinity for the dopamine D₂ receptor.

[0314] Many of the compounds have been found to inhibit the binding of[³H]Spiperone to the dopamine D₃ receptor, some of the compounds havebeen found to inhibit serotonin reuptake and some of the compounds havebeen found to be 5-HT_(2A) receptor ligands and/or 5-HT_(2C) receptorligands.

[0315] As mentioned above, the compounds of the invention have a goodaqueous solubility as compared to related compounds disclosed in WO98/28293. Accordingly, the compounds are expected to have improvedbioavailability.

[0316] Thus, the compounds of the invention are considered useful in thetreatment of positive and negative symptoms of schizophrenia, otherpsychoses, anxiety disorders, such as generalised anxiety disorder,panic disorder, and obsessive compulsive disorder, depression, sideeffects induced by conventional antipsychotic agents, migraine, ADHD andin the improvement of sleep. In particular, the compounds of theinvention are considered useful in the treatment of positive andnegative symptoms of schizophrenia without inducing extrapyramidal sideeffects.

Formulation Examples

[0317] The pharmaceutical formulations of the invention may be preparedby conventional methods in the art.

[0318] For example: Tablets may be prepared by mixing the activeingredient with ordinary adjuvants and/or diluents and subsequentlycompressing the mixture in a conventional tabletting machine. Examplesof adjuvants or diluents comprise: corn starch, potato starch, talcum,magnesium stearate, gelatine, lactose, gums, and the like. Any otheradjuvants or additives usually used for such purposes such ascolourings, flavourings, preservatives etc. may be used provided thatthey are compatible with the active ingredients.

[0319] Solutions for injections may be prepared by dissolving the activeingredient and possible additives in a part of the solvent forinjection, preferably sterile water, adjusting the solution to desiredvolume, sterilising the solution and filling it in suitable ampules orvials. Any suitable additive conventionally used in the art may beadded, such as tonicity agents, preservatives, antioxidants, etc.

[0320] Typical examples of recipes for the formulation of the inventionare as follows: 1) Tablets containing 5.0 mg of a compound of theinvention calculated as the free base: Compound 5.0 mg Lactose 60 mgMaize starch 30 mg Hydroxypropylcellulose 2.4 mg Microcrystallinecellulose 19.2 mg Croscarmellose Sodium Type A 2.4 mg Magnesium stearate0.84 mg 2) Tablets containing 0.5 mg of a compound of the inventioncalculated as the free base: Compound 0.5 mg Lactose 46.9 mg Maizestarch 23.5 mg Povidone 1.8 mg Microcrystalline cellulose 14.4 mgCroscarmellose Sodium Type A 1.8 mg Magnesium stearate 0.63 mg 3) Syrupcontaining per millilitre: Compound 25 mg Sorbitol 500 mgHydroxypropylcellulose 15 mg Glycerol 50 mg Methyl-paraben 1 mgPropyl-paraben 0.1 mg Ethanol 0.005 ml Flavour 0.05 mg Saccharin sodium0.5 mg Water ad 1 ml 4) Solution for injection containing permillilitre: Compound 0.5 mg Sorbitol 5.1 mg Acetic Acid 0.05 mgSaccharin sodium 0.5 mg Water ad 1 ml

1. A substituted indole derivative of formula I

wherein (a) one of Y¹ and Y² is N, which is bound to Y⁴, and the otherof Y¹ and Y² is CO, CS, SO, or SO₂ and Y⁴ is CH₂; (b) one of Y¹ and Y²is N, which is bound to Y⁴, and the other of Y¹ and Y² is CH₂ and Y⁴ isCO, CS, SO or SO₂; or (c) one of Y¹ and Y² is N, which is bound to Y⁴,and the other of Y¹ and Y² is CH₂ and Y⁴ is CH₂; Y³ is Z—CH₂, CH₂—Z orCH₂CH₂, and Z is O or S; provided that when Y¹ is N, Y³ may not beZ—CH₂; W is a bond or an O, S, CO, CS, SO or SO₂ group; n is 0-5, m is0-5 and m+n is 1 to 10; provided that when W is O or S, then n≧2 andm≧1; when W is CO, CS, SO or SO₂, then n≧1 and m≧1; X is C, CH or N;provided that when X is C, the dotted line indicates a bond, and when Xis N or CH, the dotted line is absent; R¹-R⁹ are independently selectedfrom hydrogen, halogen, cyano, nitro, amino, hydroxy, C₁₋₆-alkyl-amino,di-C₁₋₆-alkyl-amino, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₁₋₆alkoxy, C₁₋₆-alkylthio, C₁₋₆-alkyl substituted with hydroxy or thiol,C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, acyl, thioacyl, aryl,trifluoromethyl, trifluoromethylsulfonyl, and C₁₋₆ alkylsulfonyl; R¹⁰ ishydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₁₋₆-alkyl substitutedwith hydroxy or thiol, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,aryl, aryl-C₁₋₆-alkyl, acyl, thioacyl, C₁₋₆-alkylsulfonyl,trifluoromethylsulfonyl or arylsulfonyl, or a pharmaceuticallyacceptable acid addition salt thereof.
 2. A compound according to claim1 wherein the indole is bound to X via position 3 of the indole.
 3. Acompound according to claim 1 or 2 wherein one of Y¹ and Y² is N, whichis bound to Y⁴, and the other of Y¹ and Y² is CO, and Y⁴is CH₂.
 4. Acompound according to claim 1 or 2 wherein one of Y¹ and Y² is N, whichis bound to Y⁴, and the other of Y¹ and Y² is CH₂ and Y⁴ is CO.
 5. Acompound according to claim 1 or 2 wherein Y¹ is a nitrogen bound to Y⁴and one of Y⁴ and Y² is CO and the other is CH₂.
 6. A compound accordingto claim 3 wherein Y¹ is a nitrogen bound to Y⁴, Y² is CO and Y⁴ is CH₂.7. A compound according to claim 5 wherein Y¹ is a nitrogen bound to Y⁴,Y² is CO and Y⁴ is CH₂.
 8. A compound according to claim 4 wherein Y¹ isa nitrogen bound to Y⁴, Y² is CH₂ and Y⁴ is CO.
 9. A compound accordingto claim 5 wherein Y¹ is a nitrogen bound to Y⁴, Y² is CH₂ and Y⁴ is CO.10. A compound according to claim 1 or 2 wherein Y² is a nitrogen boundto Y⁴ and one of Y¹ and Y⁴ is CO and the other is CH₂.
 11. A compoundaccording to claim 4 wherein Y² is a nitrogen bound to Y⁴, Y¹ is CH₂ andY⁴ is CO.
 12. A compound according to claim 10 wherein Y² is a nitrogenbound to Y⁴, Y¹ is CH₂ and Y⁴ is CO.
 13. A compound according to claim 3wherein Y² is a nitrogen bound to Y⁴, Y¹ is CO and Y⁴ is CH₂.
 14. Acompound according to claim 8 wherein Y²is a nitrogen bound to Y⁴, Y¹ isCO and Y⁴ is CH₂.
 15. A compound according to claim 1 or 2 wherein oneof Y¹ and Y² is N, which is bound to Y⁴, and the other of Y¹ and Y²isCH₂ and Y⁴ is CH₂.
 16. A compound according to claim 1 wherein Y³ isCH₂CH₂ or CH₂Z.
 17. A compound according to claim 1 wherein X is C. 18.A compound according to claim 1 wherein X is N.
 19. A compound accordingto claim 1 wherein X is CH.
 20. A compound according to claim 1 whereinR¹-R⁹ are independently selected from hydrogen, halogen, cyano, nitro,amino, C₁₋₆-alkylamino, di-C₁₋₆-alkylamino, C₁₋₆-alkyl, C₃₋₈-cycloalkyland trifluoromethyl, and R¹⁰ is hydrogen, C₁₋₆-alkyl or acyl, or apharmaceutically acceptable acid addition salt thereof.
 21. A compoundaccording to claim 1 wherein W is a bond and n+m is 1 to
 6. 22. Acompound according to claim 21 wherein n+m is 3 to
 6. 23. A compoundaccording to claim 1 which is selected from:5-Fluoro-3-{1-[2-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)ethyl]piperidin-4-yl}-1H-indole;5-Fluoro-3-{1-[3-(1-oxo-3,4-dihydro-1H-quinolin-2-yl)propan-1-yl]piperidin-4-yl}-1H-indole;5-Fluoro-3-{1-[4-(1-oxo-3,4-dihydro-1H-quinolin-2-yl)butan-1-yl]piperidin-4-yl}-1H-indole;5-Fluoro-3-{1-[3-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)propan-1-yl]piperidin-4-yl}-1H-indole;5-Fluoro-3-{1-[5-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)pentan-1-yl]piperidin-4-yl}-1H-indole;5-Chloro-3-{1-[3-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)propan-1-yl]piperidin-4-yl}-1H-indole;5-Chloro-3-{1-[4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)butan-1-yl]piperidin-4-yl}-1H-indole;5-Chloro-3-{1-[5-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)pentan-1-yl]piperidin-4-yl}-1H-indole;7-Chloro-3-{1-[4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)butan-1-yl]piperidin-4-yl}-1H-indole;5-Fluoro-3-{1-[4-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl)butan-1-yl]piperidin-4-yl}-1H-indole;5-Chloro-3-{1-[4-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl)butan-1-yl]piperidin-4-yl}-1H-indole;5-Fluoro-3-{1-[3-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)propan-1-yl]-3,6-dihydro-2H-pyridin-4-yl}-1H-indole;5-Fluoro-3-{1-[4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)butan-1-yl]-3,6-dihydro-2H-pyridin-4-yl}-1H-indole;5-Fluoro-3-{1-[5-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)pentan-1-yl]-3,6-dihydro-2H-pyridin-4-yl}-1H-indole;5-Fluoro-3-{1-[4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)butan-1-yl]piperidin-4-yl}-1H-indole;5-Fluoro-1-methyl-3-{1-[3-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)propan-1-yl]piperidin-4-yl}-1H-indole;5-Fluoro-1-methyl-3-{1-[4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)butan-1-yl]piperidin-4-yl}-1H-indole;1-(Butan-1-yl)-5-fluoro-3-{1-[4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)butan-1-yl]-3,6-dihydro-2H-pyridin-4-yl}-1H-indole;5-Fluoro-3-{1-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-3-oxopropan-1-yl]piperidin-4-yl}-1H-indole;7-Chloro-3-{1-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-3-oxopropan-1-yl]piperidin-4-yl}-1H-indole;5-Chloro-3-{1-[4-(3,4-dihydro-2H-quinolin-1-yl)-4-oxobutan-1-yl]piperidin-4-yl}-1H-indole;5-Fluoro-3-{1-[4-(3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutan-1-yl]piperidin-4-yl}-1H-indole;5-Chloro-3-{1-[4-(3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutan-1-yl]piperidin-4-yl}-1H-indole;5-Fluoro-3-{1-[3-(3,4-dihydro-2H-quinolin-1-yl)propan-1-yl]piperidin-4-yl}-1H-indole;5-Fluoro-3-{1-[4-(3,4-dihydro-2H-quinolin-1-yl)butan-1-yl]piperidin-4-yl}-1H-indole;5-Fluoro-3-{1-[5-(3,4-dihydro-2H-quinolin-1-yl)pentan-1-yl]piperidin-4-yl}-1H-indole;5-Chloro-3-{1-[3-(3,4-dihydro-2H-quinolin-1-yl)propan-1-yl]piperidin-4-yl}-1H-indole;5-Chloro-3-{1-[4-(3,4-dihydro-2H-quinolin-1-yl)butan-1-yl]piperidin-4-yl}-1H-indole;5-Chloro-3-{1-[5-(3,4-dihydro-2H-quinolin-1-yl)pentan-1-yl]piperidin-4-yl}-1H-indole;7-Chloro-3-{1-[4-(3,4-dihydro-2H-quinolin-1-yl)butan-1-yl]piperidin-4-yl}-1H-indole;5-Fluoro-1-methyl-3-{1-[3-(3,4-dihydro-2H-quinolin-1-yl)propan-1-yl]piperidin-4yl}-1H-indole;5-Fluoro-1-methyl-3-{1-[4-(3,4-dihydro-2H-quinolin-1-yl)butan-1-yl]piperidin-4-yl}-1H-indole;5-Fluoro-3-{1-[4-(3,4-dihydro-2H-1,4-benzoxazin-4-yl)butan-1-yl]piperidin-4-yl}-1H-indole;5-Chloro-3-{1-[4-(3,4-dihydro-2H-1,4-benzoxazin-4-yl)butan-1-yl]piperidin-4-yl}-1H-indole;5-Fluoro-3-{1-[3-(3,4-dihydro-2H-quinolin-1-yl)propan-1-yl]-3,6-dihydro-2H-pyridin-4-yl}-1H-indole:5-Fluoro-3-{1-[4-(3,4-dihydro-2H-quinolin-1-yl)butan-1-yl]-3,6-dihydro-2H-pyridin-4-yl}-1H-indole;5-Fluoro-3-{1-[5-(3,4-dihydro-2H-quinolin-1-yl)pentan-1-yl]-3,6-dihydro-2H-pyridin-4yl}-1H-indole;4-Fluoro-3-{1-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-3-oxopropan-1-yl]piperidin-4-yl}-1H-indole;4-Fluoro-3-{1-[4-(3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutan-1-yl]piperidin-4-yl}-1H-indole;4-Fluoro-3-{1-[6-(3,4-dihydro-1H-isoquinolin-2-yl)-6-oxohexan-1-yl]piperidin-4-yl}-1H-indole;4-Chloro-3-{1-[4-(3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutan-1-yl]piperidin-4-yl}-1H-indole;4-Chloro-3-{1-[5-(3,4-dihydro-1H-isoquinolin-2-yl)-5-oxopentan-1-yl]piperidin-4-yl}-1H-indole;4-Chloro-3-{1-[6-(3,4-dihydro-1H-isoquinolin-2-yl)-6-oxohexan-1-yl]piperidin-4-yl}-1H-indole;5-Fluoro-3-{1-[5-(3,4-dihydro-1H-isoquinolin-2-yl)-5-oxopentan-1-yl]piperidin-4-yl}-1H-indole;5-Fluoro-3-{1-[6-(3,4-dihydro-1H-isoquinolin-2-yl)-6-oxohexan-1-yl]piperidin-4-yl}-6-Chloro-3-{1-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-3-oxopropan-1-yl]piperidin-4-yl}-1H-indole;6-Chloro-3-{1-[6-(3,4-dihydro-1H-isoquinolin-2-yl)-6-oxohexan-1-yl]piperidin-4-yl}-1H-indole;7-Chloro-3-{1-[4-(3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutan-1-yl]piperidin-4-yl}-1H-indole;7-Chloro-3-{1-[5-(3,4-dihydro-1H-isoquinolin-2-yl)-5-oxopentan-1-yl]piperidin-4-yl}-1H-indole;7-Chloro-3-{1-[6-(3,4-dihydro-1H-isoquinolin-2-yl)-6-oxohexan-1-yl]piperidin-4-yl}-1H-indole;4-Fluoro-3-{1-[3-(3,4-dihydro-2H-quinolin-1-yl)-3-oxopropan-1-yl]piperidin-4-yl}-1H-indole;4-Fluoro-3-{1-[4-(3,4-dihydro-2H-quinolin-1-yl)-4-oxobutan-1-yl]piperidin-4-yl}-1H-indole;4-Chloro-3-{1-[3-(3,4-dihydro-2H-quinolin-1-yl)-3-oxopropan-1-yl]piperidin-4-yl}-1H-indole;4-Chloro-3-{1-[4-(3,4-dihydro-2H-quinolin-1-yl)-4-oxobutan-1-yl]piperidin-4-yl}-1H-indole;5-Fluoro-3-{1-[3-(3,4-dihydro-2H-quinolin-1-yl)-3-oxopropan-1-yl]piperidin-4-yl}-1H-indole;5-Fluoro-3-{1-[4-(3,4-dihydro-2H-quinolin-1-yl)-4-oxobutan-1-yl]piperidin-4-yl}-1H-indole;5-Fluoro-3-{1-[5-(3,4-dihydro-2H-quinolin-1-yl)-5-oxopentan-1-yl]piperidin-4-yl}-1H-indole;5-Fluoro-3-{1-[6-(3,4-dihydro-2H-quinolin-1-yl)-6-oxohexan-1-yl]piperidin-4-yl}-1H-indole;6-Chloro-3-{1-[3-(3,4-dihydro-2H-quinolin-1-yl)-3-oxopropan-1-yl]piperidin-4-yl}-1H-indole;6-Chloro-3-{1-[6-(3,4-dihydro-2H-quinolin-1-yl)-6-oxohexan-1-yl]piperidin-4-yl}-1H-indole;7-Chloro-3-{1-[4-(3,4-dihydro-2H-quinolin-1-yl)-4-oxobutan-1-yl]piperidin-4-yl}-1H-indole;7-Chloro-3-{1-[5-(3,4-dihydro-2H-quinolin-1-yl)-5-oxopentan-1-yl]piperidin-4-yl}-1H-indole;7-Chloro-3-{1-[6-(3,4-dihydro-2H-quinolin-1-yl)-6-oxohexan-1-yl]piperidin-4-yl}-1H-indole;5-Fluoro-3-{1-[4-(3,4-dihydro-1H-isoquinolin-2-yl)butan-1-yl]piperidin-4-yl}-1H-indole;and5-Fluoro-3-{1-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)butan-1-yl]piperidin-4-yl}-1H-indoleor pharmaceutically acceptable salts thereof.
 24. A pharmaceuticalcomposition comprising a compound of claim 1 in a therapeuticallyeffective amount together with one or more pharmaceutically acceptablecarriers or diluents.
 25. A method of treating psychoses, anxietydisorders, depression, aggression, side effects induced by conventionalantipsychotic agents, migraine, cognitive disorders, ADHD and in theimprovement of sleep comprising administration of a therapeuticallyeffective amount of a compound of claim
 1. 26. The method of claim 25,wherein said psychosis is the positive and negative symptoms ofschizophrenia.
 27. The method of claim 25, wherein said anxietydisorders are selected from the group consisting of generalised anxietydisorder, panic disorder and obsessive compulsive disorder.